Processes for preparing dihydropyrimidine derivatives and intermediates thereof

ABSTRACT

The present invention refers to processes for preparing a dihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (1a), as well as a intermediate thereof. The process of the invention has simple operation, high optical purity of product, high yield and convenient work-up, which is suitable for industrial production.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a U.S. national stage application of the International PatentApplication No. PCT/CN2014/092400, filed Nov. 27, 2014, which claimspriorities to Chinese Patent Application No. 201310636920.8, filed Nov.27, 2013, and No. 201410121009.8, filed Mar. 27, 2014, all of which areincorporated herein by reference in their entirety.

FIELD

The invention refers to a chemical medicine field. Specifically, theinvention relates to processes for preparation of optically puredihydropyrimidine derivatives and optically pure dihydropyrimidineintermediates thereof.

BACKGROUND

The hepatitis B virus belongs to the family of hepadnaviridae. It cancause acute and/or persistent or progressive chronic diseases. Manyother clinical manifestations in the pathological morphology can also becaused by HBV—in particular chronic hepatitis, cirrhosis andhepatocellular carcinoma. Additionally, coinfection with hepatitis Dvirus may have adverse effects on the progress of the disease.

The conventional medicaments approved to be used for treating chronichepatitis are interferon and lamivudine. However, the interferon hasjust moderate activity but has an adverse side reaction. Althoughlamivudine has good activity, its resistance develops rapidly during thetreatment and relapse effects often appear after the treatment hasstopped. The IC50 value of lamivudine (3-TC) is 300 nM (Science, 2003,299, 893-896).

PCT Publication No. WO2008154817 discloses a series of compounds usedfor preventing, managing, treating or lessening a viral disease in apatient, particularly HBV infection or a related disease. The patentalso provides the processes for preparation of specific compounds, suchas 4-(R,S)-ethyl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylateas shown in Formula (Ib).

PCT Publication No. WO2008009210 discloses a series of optically purecompounds, which used for preventing, managing, treating or lessening anacute or chronic viral disease in a patient, particularly an acute orchronic HBV disease. The patent also provides the processes forpreparation of specific compounds, such as (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate.

Dihydropyrimidine derivatives can be prepared by several methodsdescribed in prior arts, such as patents WO1999054329, WO2008154817,WO2001068641, WO2010069147, and so on. But the process of preparation ofoptically pure dihydropyrimidine compounds described herein has not beenyet be published.

SUMMARY

The invention refers to a process for preparing a dihydropyrimidinecompound having Formula (I), or a tautomer thereof having Formula (Ia),

wherein each R¹ and R² is independently F, Cl, or Br;

R³ is C₁₋₄ alkyl;

Z is —O—, —S—, —S(═O)_(t), or —N(R⁴)—;

Y is —O—, —S—, —S(═O)_(t)—, —(CH₂)_(q)—, or —N(R⁵)—;

each t and q is independently 0, 1, or 2;

each of R⁴ and R⁵ is independently H or C₁₋₄ alkyl;

each R⁶ is independently H, deuterium, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸ or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a));

each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together withthe carbon atom to which they are attached, form a C₃₋₆ cycloalkylgroup, C₂₋₉ heterocyclyl group, or —(C═O)—;

each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl,C₁₋₄ alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or—(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H;

each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkylthio, C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or—(CR⁷R^(7a))_(m)—C(═O)O—R⁸;

R¹⁰ is H or deuterium;

n is 0, 1, 2, 3, 4, or 5; each m is independently 0, 1, 2, 3, or 4; f is1, 2, 3, or 4; and j is 0, 1, or 2.

Two preparation methods of a dihydropyrimidine compound having Formula(I) or a tautomer thereof having Formula (Ia) are depicted in thefollowing schemes,

Method One

A dihydropyrimidine compound having Formula (I), or a tautomer thereofhaving Formula (Ia) can be prepared by a general synthetic procedureillustrated through method one in Scheme 1, wherein R¹, R², Z, R⁹, j, f,R⁶, n, Y and R¹⁰ are as defined herein; wherein R^(3a) is H or C₁₋₃alkyl; R^(3b) is methoxy or ethoxy. The method one comprises thefollowing steps of: reacting a compound (VIIIa) with a compound (IX) toobtain a compound (IVa); step (A): reacting a compound (II) or a saltthereof with a compound (III) and the compound (IVa) to obtain acompound (Va) (according to some embodiments of the present invention,the reaction of the step (A) may be an one-pot reaction); step (B):halogenating the compound (Va) to form a halide; and then reacting thehalide with a compound (VI), or a salt thereof to obtain a compound(VIIa); step (C): forming a compound (I) or compound (Ia) from thecompound (VIIa) in the presence of a base (according to some embodimentsof the present invention, the reaction of the step (C) may be atransesterification).

Method Two

A dihydropyrimidine compound having Formula (I), or a tautomer thereofhaving Formula (Ia) can be prepared by a general synthetic procedureillustrated through method two in Scheme 2, wherein R¹, R², Z, R⁹, j, f,R⁶, n, Y, R¹⁰, R^(3a) and R^(3b) are as defined herein. The method twocomprises the following steps of: step (1): reacting the compound (Va)in the presence of a base to obtain a compound (X) (according to someembodiments of the present invention, the reaction of the step (1) maybe a transesterification); step (2): halogenating the compound (X) toform a halide; and then reacting the halide with a compound (VI) or asalt thereof to obtain a compound (I) or compound (Ia).

The method one depicted in scheme 1 and the method two depicted inscheme 2 comprises introducing a new chiral center to the mother nucleusof the compound, and splitting the diastereomers based on the differencein the solubility of the diastereomers; at last, removing the new chiralcenter from the mother nucleus through transesterification, then acompound may be obtained and in some embodiments of the presentinvention, the obtained compound may be optically pure. These methodshave advantages of convenient work-up, high optical purity of product,and high yield. In addition, the processes of the invention have cheapraw material, mild reaction conditions, simplified operationalprocedure, controlled safely and they are suited for industrialproduction.

The present invention also refers to an intermediate comprising adihydropyrimidine compound having Formula (Va), or a tautomer thereofhaving Formula (Va1), or a salt thereof, or a combination thereof,

wherein each R¹, R², f, Z, R⁹, j, R¹⁰, R^(3a) and R^(3b) is as definedherein.

In one aspect, provided herein is a process for preparing adihydropyrimidine compound having Formula (I), or a tautomer thereofhaving Formula (Ia) (such as the method one depicted in scheme 1)

wherein each R¹ and R² is independently F, Cl, or Br;

R³ is C₁₋₄ alkyl;

Z is —O—, —S—, —S(═O)_(t)—, or —N(R⁴)—;

Y is —O—, —S—, —S(═O)_(t)—, —(CH₂)_(q)—, or —N(R⁵)—;

each t and q is independently 0, 1, or 2;

each of R⁴ and R⁵ is independently H, or C₁₋₄ alkyl;

each R⁶ is independently H, deuterium, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a));

each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together withthe carbon atom to which they are attached, form a C₃₋₆ cycloalkylgroup, C₂₋₉ heterocyclyl group, or —(C═O)—;

each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl,C₁₋₄ alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or—(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H;

each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkylthio, C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or—(CR⁷R^(7a))_(m)—C(═O)O—R⁸;

R¹⁰ is H or deuterium;

n is 0, 1, 2, 3, 4, or 5;

each m is independently 0, 1, 2, 3, or 4;

f is 1, 2, 3, or 4;

j is 0, 1, or 2;

wherein the process comprises the steps of:

step (A): reacting an amidine compound of Formula (II), or a saltthereof with an aldehyde compound of Formula (III) and a compound ofFormula (IVa) to obtain a compound (Va) (according to some embodimentsof the present invention, the reaction of step (A) may be an one-potreaction),

wherein R^(3b) is methoxy or ethoxy; R^(3a) is H or C₁₋₃ alkyl;

step (B): halogenating the compound of Formula (Va) to form a halide;and then reacting the halide with a compound of Formula (VI), or a saltthereof to obtain a compound of Formula (VIIa),

and

step (C): forming the compound of Formula (I) or Formula (Ia) from thecompound of Formula (VIIa) by means of a transesterification, and thetransesterification may be carried out in the presence of a base.

In some embodiments, the dihydropyrimidine compound having Formula(I-1), or a tautomer thereof having Formula (Ia-1),

wherein, each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a));

each R^(7a) and R⁷ is independently H, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; and

each R¹, R², R³, Z, n, Y, m, q, R^(8a), t and R⁸ is as defined herein;

According to embodiments of present invention, the method one forpreparing the dihydropyrimidine compound having Formula (I-1), or atautomer thereof having Formula (Ia-1) comprises the steps of:

step (A) reacting an amidine compound of Formula (II-1), or a saltthereof with an aldehyde compound of Formula (III-1) and the compound ofFormula (IVa) to obtain a compound (Va-1) (according to some embodimentsof the present invention, the reaction of the step (A) may be an one-potreaction).

wherein R^(3a) and R^(3b) are as defined in Formula (Va-1) disclosedherein;

step (B): halogenating the compound of Formula (Va-1) to form a halide;and then reacting the halide with a compound of Formula (VI) or a saltthereof to obtain a compound of Formula (VIIa-1),

and

step (C): forming the compound of Formula (I-1) or Formula (Ia-1) fromthe compound of Formula (VIIa-1) by means of a transesterification,wherein the transesterification may be carried out in the presence of abase.

In some embodiments, the dihydropyrimidine compound having Formula(I-2), or a tautomer thereof having Formula (Ia-2),

wherein R¹ is F or Cl; and R² is Cl or Br; R³, Z, n, R⁶ and Y are asdefined herein;

According to embodiments of present invention, the method one forpreparing the dihydropyrimidine compound having Formula (I-2), or atautomer thereof having Formula (Ia-2) comprises the steps of:

step (A): reacting an amidine compound of Formula (II-1), or a saltthereof with an aldehyde compound of Formula (III-2) and the compound ofFormula (IVa) to obtain a compound (Va-2) (according to some embodimentsof the present invention, the reaction of the step (A) may be an one-potreaction),

wherein R^(3a) and R^(3b) are as defined in Formula (Va-1) disclosedherein;

step (B): halogenating the compound of Formula (Va-2) to form a halide;and then reacting the halide with a compound of Formula (VI), or a saltthereof to obtain a compound of Formula (VIIa-2),

and

step (C): forming the compound of Formula (I-2) or Formula (Ia-2) fromthe compound of Formula (VIIa-2) by means of a transesterification,wherein the transesterification may be carried out in the presence of abase.

According to embodiments of present invention, in the method onedisclosed herein, in some embodiments, the R³ is methyl, ethyl, propyl,isopropyl, tert-butyl, or butyl; Z is —O—, —S—, or —N(CH₃)—; Y is —O—,—S—, —S(═O)₂, or —(CH₂)_(q)—; each R⁶ is independently H, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro,triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸ or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); eachR^(7a) and R⁷ is independently H, methyl, ethyl, trifluoromethyl,—(CH₂)_(m)—OH, or —(CH²)_(m)—C(═O)O—R⁸; each R⁸ and R^(8a) isindependently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy,C₁₋₄ alkyl-S(═O)₂—, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl,isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl,triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropyl-S(═O)₂—, cyclobutyl-S(═O)₂—,cyclopentyl-S(═O)₂—, cyclohexyl-S(═O)₂—, naphthyl-S(═O)₂—,phenyl-S(═O)₂—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or—(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; R^(3b) is methoxy or ethoxy; and R^(3a)is H, methyl, ethyl, isopropyl, or propyl.

According to some embodiments of the present invention, in the methodone disclosed herein, the reaction in step (A) is performed at atemperature from 25° C. to 154° C. In some other embodiments, thereaction in step (A) is performed at a temperature from 60° C. to 100°C.

According to some embodiments of the present invention, in the methodone disclosed herein, the one-pot reaction in step (A) is performed at atemperature, in some embodiments, the reaction temperature is from 25°C. to 154° C. In other embodiments, the reaction temperature is from 30°C. to 154° C. In still other embodiments, the reaction temperature isfrom 60° C. to 100° C. In yet other embodiments, the reactiontemperature is 25° C., 30° C., 40° C., 56° C., 60° C., 64° C., 65° C.,77° C., 78° C., 80° C., 82° C., 100° C., 110° C., 120° C., 130° C., 140°C. or 154° C.

According to some embodiments of the present invention, in the methodone disclosed herein, the step (A) further comprises a step of coolingthe resulting compound of Formula (Va) of step (A) to obtain a solidcompound of Formula (Va) at a cooling temperature from −40° C. to 40° C.In some other embodiments, the cooling temperature is from 25° C. to 40°C. In some embodiments, the cooling is performed for a period of from 0hour to 24 hours. In some other embodiments, the cooling is performedfor from 1 minute to 24 hours. In still other embodiments, the coolingis performed for from 1 hour to 8 hours.

According to some embodiments of the present invention, in the methodone disclosed herein, the cooling in step (A) is carried out at atemperature, in some embodiments, the cooling temperature is from −50°C. to 60° C. In other embodiments, the cooling temperature is from −40°C. to 40° C. In other embodiments, the cooling temperature is from −30°C. to 40° C. In other embodiments, the cooling temperature is from −20°C. to 40° C. In other embodiments, the cooling temperature is from −10°C. to 40° C. In still other embodiments, the cooling temperature is from0° C. to 40° C. In yet other embodiments, the cooling temperature isfrom 25° C. to 40° C. In yet other embodiments, the cooling temperatureis −50° C., −40° C., −30° C., −20° C., −15° C., −10° C., −5° C., 0° C.,5° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 50° C. or60° C.

According to some embodiments of the present invention, in the methodone disclosed herein, the cooling temperature in step (A) is kept for aperiod of time, in some embodiments, the period of time is from 0 hourto 30 hours. In other embodiments, the period of time is from 0 hour to24 hours. In other embodiments, the period of time is from 1 minute to24 hours. In other embodiments, the period of time is from 1 hour to 12hours. In other embodiments, the period of time is from 1 hour to 10hours. In other embodiments, the period of time is from 1 hour to 8hours. In still other embodiments, the period of time is from 1 hour to6 hours. In yet other embodiments, the period of time is 0 hour, 1minute, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours,10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24hours or 30 hours.

According to some embodiments of the present invention, in the methodone disclosed herein, the amidine compound of Formula (II) reacts withthe aldehyde compound of Formula (III) and the compound of Formula (IVa)in a first organic solvent. In some embodiments, the first organicsolvent is applied in an amount of 0 equivalent to 80 equivalents per 1equivalent by weight of the amidine compound of Formula (II) or a saltthereof. In some other embodiments, the first organic solvent is appliedin an amount of 1 equivalent to 20 equivalents per 1 equivalent byweight of the amidine compound of Formula (II), or a salt thereof.

According to some embodiments of the present invention, in the methodone disclosed herein, the first organic solvent in step (A) is appliedin an amount, in some embodiments, the amount is 0 equivalent to 80equivalents per 1 equivalent by weight of an amidine compound of Formula(II), or Formula (II-1), or a salt thereof. In other embodiments, theamount is 1 equivalent to 80 equivalents per 1 equivalent by weight ofan amidine compound of Formula (II), or Formula (II-1), or a saltthereof. In other embodiments, the amount is 1 equivalent to 20equivalents per 1 equivalent by weight of an amidine compound of Formula(II), or Formula (II-1), or a salt thereof. In other embodiments, theamount is 2 equivalents to 20 equivalents per 1 equivalent by weight ofan amidine compound of Formula (II), or Formula (II-1), or a saltthereof. In other embodiments, the amount is 1 equivalent to 10equivalents per 1 equivalent by weight of an amidine compound of Formula(II), or Formula (II-1), or a salt thereof. In still other embodiments,the amount is 3 equivalents to 10 equivalents per 1 equivalent by weightof an amidine compound of Formula (II), or Formula (II-1), or a saltthereof. In yet other embodiments, the amount is 0, 1, 2, 2.5, 3, 4,4.5, 5, 6, 7, 8, 9, 10, 12, 15, 16, 18, 20, 30, 40, 50, 60, 70 or 80equivalents per 1 equivalent by weight of an amidine compound of Formula(II), or Formula (II-1), or a salt thereof.

According to some embodiments of the present invention, in the methodone disclosed herein, the step (A) further comprises a step of purifyingthe solid compound of Formula (Va). In some embodiments, the solidcompound of Formula (Va) is purified by at least one of the followingmethods: (1) trituration; (2) recrystallization; (3) washing.

According to some embodiments of the present invention, the purificationis carried out in a second organic solvent. In some embodiments, thesecond organic solvent is applied in an amount of 2 equivalent to 20equivalents per 1 equivalent by weight of the amidine compound ofFormula (II), or a salt thereof.

According to some embodiments of the present invention, in the methodone disclosed herein, the trituration is carried out at a temperaturefrom −20° C. to 50° C. In some embodiments, the trituration is carriedout at a temperature from 0° C. to 40° C.

According to some embodiments of the present invention, in the methodone disclosed herein, the recrystallization comprises a crystallizationprocess at a temperature from −30° C. to 40° C. In some embodiments, thecrystallization process is carried out at a temperature from 0° C. to40° C. In some embodiments, the recrystallization comprises acrystallization process of from 1 hour to 20 hours. In some otherembodiments, the recrystallization comprises a crystallization processof from 1 hour to 10 hours.

According to some embodiments of the present invention, in the methodone disclosed herein, the washing is performed at a temperature from 0°C. to 30° C.

According to some embodiments of the present invention, in the methodone disclosed herein, the compound of Formula (Va), Formula (Va-1), orFormula (Va-2) obtained in step (A) is further purified before step (B).In some embodiments, the compound is further purified by trituratingwith a second organic solvent. In some embodiments, the trituration iscarried out at a temperature from −20° C. to 50° C. In otherembodiments, the trituration temperature is from 0° C. to 40° C. Inother embodiments, the trituration temperature is from 5° C. to 40° C.In still other embodiments, the trituration temperature is from 25° C.to 40° C. In yet other embodiments, the trituration temperature is −20°C., −10° C., 0° C., 5° C., 10° C., 25° C., 30° C., 35° C., 40° C. or 50°C.

According to some embodiments of the present invention, in the methodone disclosed herein, the compound of Formula (Va), Formula (Va-1), orFormula (Va-2) obtained in step (A) is further purified before step (B).In some embodiments, the compound is further purified by recrystallizingfrom a second organic solvent. In some embodiments, therecrystallization has a crystallization process at a temperature from−30° C. to 50° C. In other embodiments, the crystallization temperatureis from −30° C. to 40° C. In other embodiments, the crystallizationtemperature is from −10° C. to 40° C. In other embodiments, thecrystallization temperature is from −10° C. to 30° C. In otherembodiments, the crystallization temperature is from 0° C. to 40° C. Inother embodiments, the crystallization temperature is from 0° C. to 30°C. In other embodiments, the crystallization temperature is −30° C.,−20° C., −10° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C.,35° C., 40° C. or 50° C. In some embodiments, the recrystallization hasa crystallization process taking a period of time from 1 hour to 20hours. In other embodiments, the period of time is from 2 hours to 18hours. In still other embodiments, the period of time is from 1 hour to10 hours. In yet other embodiments, the period of time is 1 hour, 2hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10hours, 12 hours, 14 hours, 16 hours, 18 hours or 20 hours.

According to some embodiments of the present invention, in the methodone disclosed herein, the compound of Formula (Va), Formula (Va-1), orFormula (Va-2) obtained in step (A) is further purified before step (B).In some embodiments, the compound is further purified by washing with asecond organic solvent. In some embodiments, the washing is performed ata temperature from 5° C. to 40° C. In other embodiments, the washingtemperature is from 0° C. to 30° C. In still other embodiments, thewashing temperature is −20° C., −10° C., 0° C., 10° C., 20° C., 25° C.,30° C., 35° C., 40° C. or 50° C.

According to some embodiments of the present invention, in the methodone disclosed herein, the second organic solvent used in the furtherpurification before step (B) is applied in an amount, in someembodiments, the amount is about 0 equivalent to 20 equivalents per 1equivalent by weight of an amidine compound of Formula (II), or Formula(II-1), or a salt thereof. In other embodiments, the amount is about 1equivalent to 20 equivalents per 1 equivalent by weight of an amidinecompound of Formula (II), or Formula (II-1), or a salt thereof. In otherembodiments, the amount is about 2 equivalents to 20 equivalents per 1equivalent by weight of an amidine compound of Formula (II), or Formula(II-1), or a salt thereof. In other embodiments, the amount is about 2equivalents to 15 equivalents per 1 equivalent by weight of an amidinecompound of Formula (II), or Formula (II-1), or a salt thereof. In stillother embodiments, the amount is about 2 equivalents to 10 equivalentsper 1 equivalent by weight of an amidine compound of Formula (II), orFormula (II-1), or a salt thereof. In yet other embodiments, the amountis about 0, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 7.5, 8, 9, 10, 12, 13, 15,16, 18, 20, 30, 40, 50, 60, 70 or 80 equivalents per 1 equivalent byweight of an amidine compound of Formula (II), or Formula (II-1), or asalt thereof.

According to some embodiments of the present invention, in the methodone disclosed herein, in some embodiments, each of the first organicsolvent and the second organic solvent is independently a C₁₋₄ alcohol,a C₁₋₄ alcohol-water, acetone, diethyl ether, isopropyl ether, petroleumether, tetrahydrofuran, acetonitrile, cyclopentane, cyclohexane,n-hexane, a C₁₋₄ haloalkane, ethyl acetate, trifluoroethanol,2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether,N,N-dimethyl formamide, N-methylpyrolidone, or a combination thereof. Inother embodiments, each of the first organic solvent and the secondorganic solvent is independently methanol, ethanol, n-propanol,i-propanol, n-butanol, tert-butanol, an ethanol-water mixture at avolume ratio of from 10:90 to 90:10, an ethanol-water mixture at avolume ratio of 50:50, acetone, tetrahydrofuran, N-methylpyrolidone,trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethylether, ethyl acetate, glycol, N,N-dimethyl formamide, or a combinationthereof.

According to some embodiments of the present invention, in the methodone disclosed herein, the halogenating in step (B) is carried out in athird organic solvent, in some embodiments, the third organic solvent isone or more C₁₋₄ alcohols, one or more C₁₋₄ haloalkanes, acetonitrile,isopropyl ether, petroleum ether, toluene, xylene, tetrahydrofuran,ethyl acetate, acetone, or a combination thereof. In other embodiments,the third organic solvent is dichloromethane, chloroform,tetrachloromethane, acetonitrile, isopropyl ether, petroleum ether,tetrahydrofuran, methanol, ethanol, propanol, i-propanol, n-butanol,tert-butanol, ethyl acetate, acetone, or a combination thereof.

According to some embodiments of the present invention, the method onedisclosed herein, in some embodiments, the halogenating reaction in step(B) is carried out in the presence of a halogenating agent, and whereinthe halogenating agent is N-bromosuccinimide, N-chlorosuccinimide,N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof.

According to some embodiments of the present invention, the method onedisclosed herein, in some embodiments, the base used in step (C) isformed by reacting lithium, sodium, or potassium or a combinationthereof with a C₁₋₄ alcohol.

According to some embodiments of the present invention, the method onedisclosed herein, in some embodiments, the C₁₋₄ alcohol for forming thebase used in step (C) by reacting with lithium, sodium, or potassium, ora combination thereof is methanol, ethanol, propanol, i-propanol,n-butanol, i-butanol, or tert-butanol.

According to some embodiments of the present invention, the method onedisclosed herein, each of the lithium, sodium and potassium or acombination thereof for forming a base used in step (C) by reacting witha C₁₋₄ alcohol is independently applied in an amount, in someembodiments, the amount is 0.1 equivalent to 10 equivalents per 1equivalent by mole of a compound of Formula (VIIa), Formula (VIIa-1), orFormula (VIIa-2). In other embodiments, the amount is 2 equivalents to 6equivalents per 1 equivalent by mole of a compound of Formula (VIIa),Formula (VIIa-1), or Formula (VIIa-2). In still other embodiments, theamount is 2.5 equivalents to 6 equivalents per 1 equivalent by mole of acompound of Formula (VIIa), Formula (VIIa-1), or Formula (VIIa-2). Inyet other embodiments, the amount is 0.1, 0.5, 1, 2, 2.5, 3, 3.5, 4, 5,6, 7, 8, 9 or 10 equivalents per 1 equivalent by mole of a compound ofFormula (VIIa), Formula (VIIa-1), or Formula (VIIa-2).

According to some embodiments of the present invention, the method onedisclosed herein, in some embodiments, the compound of Formula (IVa) instep (A) is prepared by a process comprising reacting a compound ofFormula (VIIIa) with a compound of Formula (IX),

wherein R^(3a) and R^(3b) are as defined herein.

In one aspect, provided herein is an intermediate comprising adihydropyrimidine compound having Formula (Va), or a tautomer thereofhaving Formula (Va1), or a salt thereof, or a combination thereof,

wherein each R¹ and R² is independently F, Cl, or Br;

R^(3b) is methoxy or ethoxy;

R^(3a) is H or C₁₋₃ alkyl;

each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ alkylthio, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or—(CR⁷R^(7a))_(m)—C(═O)O—R⁸;

each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together withthe carbon atom to which they are attached, form a C₃₋₆ cycloalkylgroup, C₂₋₉ heterocyclyl group, or —(C═O)—;

each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl,C₁₋₄ alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or—(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H;

each m is independently 0, 1, 2, 3, or 4;

R¹⁰ is H or deuterium;

f is 1, 2, 3, or 4;

j is 0, 1, or 2;

Z is —O—, —S—, —S(═O)_(t), or —N(R⁴)—;

t is 0, 1, or 2; and

R⁴ is H or C₁₋₄ alkyl;

In some embodiments, provided herein is the intermediate having Formula(Va-1), or a tautomer thereof having Formula (Va1-1), or a salt thereof,or a combination thereof,

wherein R^(3a), R^(3b), R¹, R² and Z are as defined herein.

In some embodiments, provided herein is the intermediate having Formula(Va-2), or a tautomer thereof having Formula (Va1-2), or a salt thereof,or a combination thereof,

wherein R¹ is F or Cl; and R² is Cl or Br;

Z is —O—, —S—, or —N(CH₃)—;

R^(3b) is methoxy or ethoxy; and

R^(3a) is H, methyl, ethyl, isopropyl, or propyl.

In other aspect, provided herein is a process for preparing adihydropyrimidine compound having Formula (I), or a tautomer thereofhaving Formula (Ia), or a combination thereof, (such as the method twodepicted in scheme 2),

wherein each R¹ and R² is independently F, Cl, or Br;

R³ is C₁₋₄ alkyl;

Z is —O—, —S—, —S(═O)_(t)—, or —N(R⁴)—;

Y is —O—, —S—, —S(═O)_(t)—, —(CH₂)q-, or —N(R⁵)—;

each t and q is independently 0, 1, or 2;

each of R⁴ and R⁵ is independently H, or C₁₋₄ alkyl;

each R⁶ is independently H, deuterium, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—(C═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a));

each R^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together withthe carbon atom to which they are attached, form a C₃₋₆ cycloalkylgroup, C₂₋₉ heterocyclyl group, or —(C═O)—;

each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl,C₁₋₄ alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or—(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H;

each R⁹ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ alkylthio, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or—(CR⁷R^(7a))_(m)—C(═O)O—R⁸;

R¹⁰ is H or deuterium;

n is 0, 1, 2, 3, 4, or 5;

each m is independently 0, 1, 2, 3, or 4;

f is 1, 2, 3, or 4; and

j is 0, 1, or 2;

wherein the process comprises the steps of:

step (1): reacting an amidine compound of Formula (II), or a saltthereof with an aldehyde compound of Formula (III) and a compound ofFormula (IVa) to obtain a compound (Va) (according to some embodimentsof present invention, the reaction of the step (A) may be, but notlimited to an one-pot reaction),

step (2): forming a compound of Formula (X) from a compound of Formula(Va) by means of a transesterification, and the transesterification maybe carried out in the presence of a base,

wherein R^(3b) is methoxy or ethoxy; and

R^(3a) is H or C₁₋₃ alkyl;

step (3): halogenating the compound of Formula (X) to form a halide; andthen reacting the halide with a compound of Formula (VI), or a saltthereof to obtain a compound of Formula (I) or Formula (Ia).

In other embodiments, the dihydropyrimidine compound having Formula(I-1), or a tautomer thereof having Formula (Ia-1),

wherein each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a));

each R^(7a) and R⁷ is independently H, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; and

each R¹, R², R³, Z, n, Y, m, q, R^(8a), t and R⁸ is as defined herein;

According to some embodiments of the present invention, the method twofor preparing the optically pure dihydropyrimidine compound havingFormula (I-1), or a tautomer thereof having Formula (Ia-1) comprises thesteps of:

step (1): reacting an amidine compound of Formula (II-1), or a saltthereof with an aldehyde compound of Formula (III-1) and the compound ofFormula (IVa) to obtain a compound (Va-1) (according to some embodimentsof present invention, the reaction of the step (A) may be an one-potreaction).

step (2): forming a compound of Formula (X-1) from a compound of Formula(Va-1) by means of a transesterification, wherein thetransesterification may be carried out in the presence of a base,

wherein R^(3a) and R^(3b) are as defined herein;

step (3): halogenating the compound of Formula (X-1) to form a halide;and then reacting the intermediate with a compound of Formula (VI), or asalt thereof to obtain a compound of Formula (I-1) or Formula (Ia-1).

In other embodiments, the dihydropyrimidine compound having Formula(I-2), or a tautomer thereof having Formula (Ia-2),

wherein R¹ is F or Cl; and R² is Cl or Br; R³, Z, n, Y and R⁶ are asdefined herein;

According to some embodiments of the present invention, the method twofor preparing the dihydropyrimidine compound having Formula (I-2), or atautomer thereof having Formula (Ia-2) comprises the steps of:

step (1): reacting an amidine compound of Formula (II-1), or a saltthereof with an aldehyde compound of Formula (III-2) and the compound ofFormula (IVa) to obtain a compound (Va-2) (according to some embodimentsof the present invention, the reaction of the step (A) may be an one-potreaction),

step (2): forming a compound of Formula (X-2) from a compound of Formula(Va-2) by means of a transesterification, wherein thetransesterification may be carried out in the presence of a base,

wherein R^(3a) and R^(3b) are as defined herein;

step (3): halogenating the compound of Formula (X-2) to form a halide;and then reacting the halide with a compound of Formula (VI), or a saltthereof to obtain a compound of Formula (I-2) or Formula (Ia-2).

According to some embodiments of the present invention, in the methodtwo disclosed herein, in some embodiments, the R³ is methyl, ethyl,propyl, isopropyl, tert-butyl, or butyl; Z is —O—, —S—, or —N(CH₃)—; Yis —O—, —S—, —S(═O)₂, or —(CH₂)_(q)—; each R⁶ is independently H, halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro,triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸ or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); eachR^(7a) and R⁷ is independently H, methyl, ethyl, trifluoromethyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; each R⁸ and R^(8a) isindependently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy,C₁₋₄ alkyl-S(═O)₂—, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl,isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl,triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropyl-S(═O)₂—, cyclobutyl-S(═O)₂—,cyclopentyl-S(═O)₂—, cyclohexyl-S(═O)₂—, naphthyl-S(═O)₂—,phenyl-S(═O)₂—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or—(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; R^(3b) is methoxy or ethoxy; and R^(3a)is H, methyl, ethyl, isopropyl, or propyl.

According to some embodiments of the present invention, in the methodtwo disclosed herein, the reaction in step (1) is performed at atemperature from 25° C. to 154° C. In some other embodiments, thereaction in step (1) is performed at a temperature from 60° C. to 100°C.

According to some embodiments of the present invention, in the methodtwo disclosed herein, the step (1) further comprises the step of coolingthe resulting compound (Va) of step (1) to obtain a solid compound (Va)at a cooling temperature from −40° C. to 40° C. In other embodiments,the cooling temperature is from 25° C. to 40° C. In some embodiments,the cooling is performed for a period of from 0 hour to 24 hours. Insome other embodiments, the cooling is performed for from 1 minute to 24hours. In still other embodiments, the cooling is performed for from 1hour to 8 hours.

According to some embodiments of the present invention, in the methodtwo disclosed herein, the amidine compound of Formula (II) reacts withthe aldehyde compound of Formula (III) and the compound of Formula (IVa)in a first organic solvent. In some embodiments, the first organicsolvent is applied in an amount of 0 equivalent to 80 equivalents per 1equivalent by weight of the amidine compound of Formula (II), or a saltthereof. In some other embodiments, the first organic solvent is appliedin an amount of 1 equivalent to 20 equivalents per 1 equivalent byweight of the amidine compound of Formula (II), or a salt thereof.

According to some embodiments of the present invention, in the methodtwo disclosed herein, step (1) further comprises the step of purifyingthe solid compound (Va). In some embodiments, the solid compound ofFormula (Va) is purified by at least one of the following methods: (1)trituration; (2) recrystallization; (3) washing.

According to some embodiments of the present invention, the purificationis carried out in a second organic solvent. In some embodiments, thesecond organic solvent is applied in an amount of 2 equivalent to 20equivalents per 1 equivalent by weight of the amidine compound ofFormula (II), or a salt thereof.

According to some embodiments of the present invention, in the methodtwo disclosed herein, the trituration is carried out at a temperaturefrom −20° C. to 50° C. In some embodiments, the trituration is carriedout at a temperature from 0° C. to 40° C.

According to some embodiments of the present invention, in the methodtwo disclosed herein, the recrystallization comprises a crystallizationprocess at a temperature from −30° C. to 40° C. In some embodiments, thecrystallization process is carried out at a temperature from 0° C. to40° C. In some embodiments, the recrystallization comprises acrystallization process of from 1 hour to 20 hours. In some otherembodiments, the recrystallization comprises a crystallization processof from 1 hour to 10 hours.

According to some embodiments of the present invention, in the methodtwo disclosed herein, the washing is performed at a temperature from 0°C. to 30° C.

According to some embodiments of the present invention, in the methodtwo disclosed herein, in some embodiments, each of the first organicsolvent and the second organic solvent is independently a C₁₋₄ alcohol,a C₁₋₄ alcohol-water, acetone, diethyl ether, isopropyl ether, petroleumether, tetrahydrofuran, acetonitrile, cyclopentane, cyclohexane,n-hexane, C₁₋₄ haloalkanes solvent, ethyl acetate, trifluoroethanol,2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether,N,N-dimethyl formamide, N-methylpyrolidone, or a combination thereof. Insome other embodiments, each of the first organic solvent and the secondorganic solvent is independently methanol, ethanol, n-propanol,i-propanol, n-butanol, tert-butanol, an ethanol-water mixture at avolume ratio from 10:90 to 90:10, an ethanol-water mixture at a volumeratio from 50:50, acetone, tetrahydrofuran, N-methylpyrolidone,trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethylether, ethyl acetate, glycol, N,N-dimethyl formamide, or a combinationthereof.

According to some embodiments of the present invention, in the methodtwo disclosed herein, in some embodiments, the base used in step (2) isformed by reacting lithium, sodium, or potassium or a combinationthereof with a C₁₋₄ alcohol.

According to some embodiments of the present invention, in the methodtwo disclosed herein, in some embodiments, the C₁₋₄ alcohol for formingthe base used in step (2) by reacting with lithium, sodium, orpotassium, or a combination thereof is methanol, ethanol, propanol,i-propanol, n-butanol, i-butanol, or tert-butanol.

According to some embodiments of the present invention, in the methodtwo disclosed herein, each of the lithium, sodium and potassium, or acombination thereof for forming the base used in step (2) by reactingwith a C₁₋₄ alcohol is independently applied in an amount, in someembodiments, the amount is 0.5 equivalent to 10 equivalents per 1equivalent by mole of a compound of Formula (Va), Formula (Va-1), orFormula (Va-2). In other embodiments, the amount is 2 equivalents to 8equivalents per 1 equivalent by mole of a compound of Formula (Va),Formula (Va-1), or Formula (Va-2). In still other embodiments, theamount is 2.5 equivalents to 8 equivalents per 1 equivalent by mole of acompound of Formula (Va), Formula (Va-1), or Formula (Va-2). In yetother embodiments, the amount is 0.5, 1, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9or 10 equivalents per 1 equivalent by mole of a compound of Formula(Va), Formula (Va-1), or Formula (Va-2).

According to some embodiments of the present invention, in the methodtwo disclosed herein, the halogenating reaction in step (3) is carriedout in a forth organic solvent, in some embodiments, the forth organicsolvent is one or more C₁₋₄ alcohols, one or more C₁₋₄ haloalkanes,ethyl acetate, acetonitrile, isopropyl ether, petroleum ether, toluene,xylene, tetrahydrofuran, acetone, or a combination thereof. In otherembodiments, the forth organic solvent is dichloromethane, chloroform,tetrachloromethane, acetonitrile, isopropyl ether, petroleum ether,tetrahydrofuran, methanol, ethanol, propanol, i-propanol, n-butanol,tert-butanol, ethyl acetate, acetone, or a combination thereof.

According to some embodiments of the present invention, in the methodtwo disclosed herein, in some embodiments, the halogenating reaction instep (2) is carried out in the presence of a halogenating agent, andwherein the halogenating agent is N-bromosuccinimide,N-chlorosuccinimide, N-iodosuccinimide,1,3-dibromo-5,5-dimethylhydantoin, or1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof.

DEFINITIONS AND GENERAL TERMINOLOGY

The term “alkyl” or “alk-” or “alkyl group” as used interchangeably inthe context of the present invention, such as in alkyl, aminoalkyl,alkyamino, alkylthio or alkoxy, refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of 1 to 10 carbon atoms.Wherein, the alkyl group may be optionally substituted with one or moresubstituents disclosed herein. In some embodiments, the alkyl groupcontains 1-10 carbon atoms. In other embodiments, the alkyl groupcontains 1-6 carbon atoms. In other embodiments, the alkyl groupcontains 1-4 carbon atoms. In still other embodiments, the alkyl groupcontains 1-3 carbon atoms.

Some non-limiting examples of the alkyl group include, methyl (Me,—CH₃), ethyl (Et, —CH₂CH₃), n-propyl (n-Pr, —CH₂CH₂CH₃), isopropyl(i-Pr, —CH(CH₃)₂), n-butyl (n-Bu, —CH₂CH₂CH₂CH₃), isobutyl (i-Bu,—CH₂CH(CH₃)₂), sec-butyl (s-Bu, —CH(CH₃)CH₂CH₃), tert-butyl (t-Bu,—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃),3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂),2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃),2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, n-heptyl and n-octyl, etc.

The term “aminoalkyl” refers to a C₁₋₁₀ linear or branched-chain alkylgroup substituted with one or more amino groups. In some embodiments,the aminoalkyl group refers to a C₁₋₆ aminoalkyl group, wherein thealkyl group is as defined herein. Some non-limiting examples of theaminoalkyl group include aminomethyl, 2-aminoethyl, 2-aminoisopropyl,aminopropyl, aminobutyl and aminohexyl, etc.

The term “alkoxy” refers to an alkyl group attached to the rest part ofthe molecule through an oxygen atom, wherein the alkyl group is asdefined herein. Unless otherwise specified, the alkoxy group contains1-10 carbon atoms. In some embodiments, the alkoxy group contains 1-6carbon atoms. In other embodiments, the alkoxy group contains 1-4 carbonatoms. In still other embodiments, the alkoxy group contains 1-3 carbonatoms. Some non-limiting examples of the alkoxy group include methoxy(MeO, —OCH₃), ethoxy (EtO, —OCH₂CH₃), propoxy (n-PrO, n-propoxy,—OCH₂CH₂CH₃), isopropoxy (i-PrO, i-propoxy, —OCH(CH₃)₂), n-butoxy(n-BuO, —OCH₂CH₂CH₂CH₃), 1-methyl-propoxy (s-BuO, s-butoxy,—OCH(CH₃)CH₂CH₃), 2-methyl-1-propoxy (i-BuO, i-butoxy, —OCH₂CH(CH₃)₂),tert-butoxy (t-BuO, t-butoxy, —OC(CH₃)₃), n-pentoxy (—OCH₂CH₂CH₂CH₂CH₃),2-pentoxy (—OCH(CH₃)CH₂CH₂CH₃), 3-pentoxy (—OCH(CH₂CH₃)₂),2-methyl-2-butoxy (—OC(CH₃)₂CH₂CH₃), 3-methyl-2-butoxy(—OCH(CH₃)CH(CH₃)₂), 3-methyl-1-butoxy (—OCH₂CH₂CH(CH₃)₂),2-methyl-1-butoxy (—OCH₂CH(CH₃)CH₂CH₃) and n-hexyloxy(—OCH₂CH₂CH₂CH₂CH₂CH₃), etc.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” respectively referto alkyl, alkenyl or alkoxy, as the case may be, substituted with one ormore halogen atoms. Wherein the alkyl, alkenyl and alkoxy are as definedherein. Some non-limiting examples of these groups include —CF₃, —CH₂Cl,—CH₂CF₃, —CH₂CH₂CF₃, —OCF₃, —OCHF₂, —OCHCl₂, —OCH₂CHF₂, —OCH₂CHCl₂ and—OCH(CH₃)CHF₂, etc.

The term “alkylamino” refers to “N-alkylamino” and “N,N-dialkylamino”wherein amino groups are independently substituted with one alkylradical or two alkyl radicals, respectively. Wherein the amino group andthe alkyl group are as defined herein. In some embodiments, thealkylamino radical is “lower alkylamino” radical having one or two C₁₋₆alkyl groups attached to a nitrogen atom. In other embodiments, thealkylamino radical refers to C₁₋₄ lower alkylamino group. In still otherembodiments, the alkylamino radical refers to C₁₋₃ lower alkylaminogroup. Some non-limiting examples of suitable alkylamino radical includemono or dialkylamino. Some examples include, but are not limited to,methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino,n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino,N,N-dimethylamino and N,N-diethylamino, etc.

The term “alkylthio” refers to a radical containing a linear orbranched-alkyl radical of one to ten carbon atoms, attached to adivalent sulfur atom. Wherein the alkyl group is as defined herein. Somenon-limiting examples of the alkylthio group include methylthio (CH₃S—)and ethylthio, etc.

The term “cycloalkyl” refers to a monovalent or multivalent saturatedring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclicring system. Wherein, the cycloalkyl group may be optionally substitutedwith one or more substituents disclosed herein. In some embodiments, thecycloalkyl contains 3 to 12 carbon atoms. In still other embodiments,the cycloalkyl contains 3 to 8 carbon atoms. In yet other embodiments,the cycloalkyl contains 3 to 6 carbon atoms. Some examples include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclohendecyl andcyclododecyl, etc.

The term “cycloalkylalkyl” refers to an alkyl radical substituted withone or more cycloalkyl radicals, wherein the cycloalkyl and alkyl are asdefined herein. Some non-limiting examples of the cycloalkylalkyl groupinclude cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl,cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl,cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyland cyclohexylpropyl, etc.

The term “cycloalkyloxy” or “cycloalkoxy” refers to a cycloalkyl group,attached to the rest part of the molecule through an oxygen atom.Wherein the cycloalkyl group is as defined herein. Some non-limitingexamples of the cycloalkyloxy group include cyclopropoxy, cyclopentyloxyand cyclohexyloxy, etc.

The term “cycloalkylamino” refers to an amino group is substituted withone or two cycloalkyl radicals. Some non-limiting examples of suchradical include cyclopropylamino, cyclobutylamino, cyclopentylamino andcyclohexylamino, etc. In some embodiments, the cycloalkyl ofcycloalkylamino group may be optionally substituted with one or moresubstituents disclosed herein.

The term “heterocyclyl” refers to a saturated or unsaturation,nonaromatic, monocyclic, bicyclic or tricyclic ring system in which atleast one ring member is selected from nitrogen, sulfur and oxygen.Wherein, the heterocyclyl group may be optionally substituted with oneor more substituents disclosed herein. Unless otherwise specified, theheterocyclyl group may be carbon or nitrogen linked, and a —CH₂— groupcan be optionally replaced by a —C(═O)— group. In which, the sulfur canbe optionally oxygenized to S-oxide and the nitrogen can be optionallyoxygenized to N-oxide. In some embodiments, the heterocyclyl group maybe a C₂₋₁₀ heterocyclyl group, which refers to a heterocyclyl groupcontaining 2 to 10 carbon atoms and at least one heteroatom selectedfrom nitrogen, sulfur and oxygen. In other embodiments, the heterocyclylgroup may be a C₂₋₉ heterocyclyl group, which refers to a heterocyclylgroup containing 2 to 9 carbon atoms and at least one heteroatomselected from nitrogen, sulfur and oxygen. In still other embodiments,the heterocyclyl group may be a C₂₋₇ heterocyclyl group, which refers toan heterocyclyl group containing 2 to 7 carbon atoms and at least oneheteroatom selected from nitrogen, sulfur and oxygen. In yet otherembodiments, the heterocyclyl group may be a C₂₋₅ heterocyclyl group,which refers to a heterocyclyl group containing 2 to 5 carbon atoms andat least one heteroatom selected from nitrogen, sulfur and oxygen. Somenon-limiting examples of the heterocyclyl group include oxiranyl,thietanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dihydrothienyl,dihydropyranyl, piperidinyl, morpholinyl, tetrahydropyrimidinyl,oxazinanyl, thiomorpholinyl and piperazinyl, etc. A —CH₂— group of theheterocyclyl group may be substituted with —C(═O), some non-limitingexamples of such group include 2-oxopyrrolidinyl, 2-piperidinonyl,3-morpholinonyl, 3-thiomorpholinonyl and oxotetrahydropyrimidinyl, etc.

The term “heterocyclylalkyl” refers to a heterocyclyl group attached tothe rest of the molecule through an alkyl group, wherein theheterocyclyl and alkyl are as defined herein. Some non-limiting examplesof such group included pyrrolidinylmethyl, piperidinylmethyl,piperidinylethyl, morpholinylmethyl and morpholinylethyl, etc.

The term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br)or iodine (I).

The term “aryl” refers to monocyclic, bicyclic and tricyclic carbocyclicring systems having a total of six to fourteen ring members, or six totwelve ring members, or six to ten ring members, wherein at least onering in the system is aromatic, wherein each ring in the system contains3 to 7 ring members and that has a single point or multipoint ofattachment to the rest of the molecule. Wherein the aryl may beoptionally substituted with the substituent disclosed herein. The term“aryl” and “aromatic ring” can be used interchangeably herein. Somenon-limiting examples of the aryl group include phenyl,2,3-dihydro-1H-indenyl, naphthalenyl and anthracenyl, etc.

The term “arylalkyl” or “aralkyl” refers to an aryl group attached tothe rest of the molecule through an alkyl group, wherein the aryl andalkyl are as defined herein. Some non-limiting examples of such groupinclude benzyl, phenylethyl and naphthalenylmethyl, etc.

The term “arylamino” refers to an amino group substituted with one ortwo aryl groups. Some non-limiting examples of such group includedN-phenylamino. In some embodiments, the aryl group of the arylamino maybe further substituted.

The term “heteroaryl” refers to monocyclic, bicyclic and tricycliccarbocyclic ring systems having a total of five to twelve ring members,or five to ten ring members, or five to six ring members, wherein atleast one ring in the system is aromatic, and in which at least one ringmember is selected from nitrogen, sulfur and oxygen, and wherein eachring in the system contains 3 to 7 ring members and that has a singlepoint or multipoint of attachment to the rest of the molecule. The term“heteroaryl” and “heteroaromatic ring” or “heteroaromatic compound” canbe used interchangeably herein. In other embodiments, the heteroarylgroup may be a C₁₋₉ heteroaryl group, which refers to a heteroaryl groupcontaining 1 to 9 carbon atoms and at least one heteroatom selected fromnitrogen, sulfur and oxygen. In other embodiments, the heteroaryl groupmay be a C₁₋₇ heteroaryl group, which refers to a heteroaryl groupcontaining 1 to 7 carbon atoms and at least one heteroatom selected fromnitrogen, sulfur and oxygen. In still other embodiments, the heteroarylgroup may be a C₁₋₆ heteroaryl group, which refers to a heteroaryl groupcontaining 1 to 6 carbon atoms and at least one heteroatom selected fromnitrogen, sulfur and oxygen. In other embodiments, the heteroaryl groupmay be a C₁₋₅ heteroaryl group, which refers to a heteroaryl groupcontaining 1 to 5 carbon atoms and at least one heteroatom selected fromnitrogen, sulfur and oxygen. In still other embodiments, the heteroarylgroup may be a C₁₋₄ heteroaryl group, which refers to a heteroaryl groupcontaining 1 to 4 carbon atoms and at least one heteroatom selected fromnitrogen, sulfur and oxygen. In yet other embodiments, the heteroarylgroup may be a C₁₋₃ heteroaryl group, which refers to a heteroaryl groupcontaining 1 to 3 carbon atoms and at least one heteroatom selected fromnitrogen, sulfur and oxygen. Some non-limiting examples of such groupinclude furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, diazolyl,triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyranyl and triazinyl, etc, and also include the followingbicycle ring, but are not limited to: benzimidazolyl, benzofuranyl,benzothiophenyl, indolyl, oxoindolyl, indolinyl, imidazopyridyl,pyrazopryridyl, pyrazopyrimidinyl, quinolyl, isoquinolyl andquinazolinyl, etc. The heteroaryl group may be optionally substitutedwith one or more substituents disclosed herein.

The term “heteroarylalkyl” refers to an heteroaryl group attached to therest of the molecule through a alkyl group, wherein the heteroaryl andalkyl are as defined herein. The “heteroarylalkyl” group may beoptionally substituted with one or more substituents disclosed herein.Some non-limiting examples of such group included pyridylmethyl,pyrrolylethyl and quinolylmethyl, etc.

The term “comprise” is an open expression, it means comprising thecontents disclosed herein, but don't exclude other contents.

Furthermore, unless otherwise stated, the phrase “each . . . isindependently” is used interchangeably with the phrase “each (of) . . .and . . . is independently”. It should be understood broadly that thespecific options expressed by the same symbol are independently of eachother in different radicals; or the specific options expressed by thesame symbol are independently of each other in same radicals. Such asFormula (a), multiple n are independently of each other, multiple R⁶ areindependently of each other,

As described herein, a system containing a group formed by connecting adouble bond with a wave bond indicates that it is (Z) or (E)configuration, or a combination thereof.

The solvent used for the reaction of the invention is not particularlyrestricted, any solvent is contained in the invention so long as it candissolve the raw materials to a certain extent and doesn't inhibit thereaction. Additionally, many similar modifications in the art,substitutions to same object, or solvent, solvent composition and thesolvent composition with different proportions which are equivalent tothose described in the invention, all are deemed to be included in thepresent invention. Wherein the solvent could be alcohols, alcohol-watermixtures, ethers, halohydrocarbons, esters, ketones, aromatichydrocarbons, alkanes, acetonitrile, trifluoroethanol, N,N-dimethylformamide (DMF), N-methylpyrolidone (NMP), or a combination thereof.Such as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol,a ethanol-water mixture at a volume ratio of 50:50, trifluoroethanol,tert-butanol, petroleum ether, n-pentane, n-hexane, n-heptane,cyclohexane, isopropyl ether, DMF, tetrahydrofuran, ethyl ether,dioxane, methyl tertiary butyl ether (MTBE), 1,2-dimethoxylethane, NMP,2-methoxyethanol, 1,2-dimethoxyethane, diethylene glycol dimethyl ether,triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane,chloroform, tetrachloromethane, ethyl acetate, isopropyl acetate,acetone, butanone, benzene, toluene, xylene or a combination thereof.

The amount of water in the solvent is not particularly restricted. Solong as the solvent containing a certain amount of water can be used inthe reaction disclosed herein, which is deemed to be included in thepresent invention. The amount of water in the solvent is approximatelyless than 0.05%, less than 0.1%, less than 0.2%, less than 0.5%, lessthan 5%, less than 10%, less than 25%, less than 30%, or 0%.

The solvent used for the recrystallization of the invention is notparticularly restricted, any solvent is contained in the invention solong as it can dissolve the crude product and the crystal product canprecipitate out under certain conditions. Additionally, many similarmodifications in the art, substitutions to same object, or solvent,solvent composition and the solvent composition with differentproportions which are equivalent to those described in the invention,all are deemed to be included in the present invention. Wherein thesolvent could be alcohols, alcohol-water mixtures, ethers, alkanes,halohydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile,N,N-dimethyl formamide (DMF), N-methylpyrolidone (NMP), or a combinationthereof. Such as methanol, ethanol, n-propanol, i-propanol, n-butanol,i-butanol, tert-butanol, trifluoroethanol, a ethanol-water mixture at avolume ratio of 50:50, petroleum ether, n-pentane, n-hexane, n-heptane,cyclohexane, DMF, tetrahydrofuran, ethyl ether, isopropyl ether,dioxane, methyl tertiary butyl ether (MTBE), 1,2-dimethoxylethane, NMP,2-methoxyethanol, 1,2-dimethoxyethane, diethylene glycol dimethyl ether,triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane,chloroform, tetrachloromethane, ethyl acetate, isopropyl acetate,acetone, butanone, benzene, toluene, xylene or a combination thereof.

Any temperature is included in the present invention so long as it isapplicable for the one-pot reaction. Additionally, many similarmodifications in the art, substitutions to same object, or temperatureand temperature scope which are equivalent to those described in theinvention, all are deemed to be included in the present invention. Insome embodiments, the one-pot reaction temperature is from approximatelyroom temperature (usually 25° C.) to 154° C. The reaction is carried outat a low temperature at the beginning or at the earlier stage, afterrising of the temperature, the reaction is carried out at a highertemperature, which may be from approximately 25° C. to solvent boilingpoint, from approximately 30° C. to solvent boiling point, fromapproximately 25° C. to 154° C., or from approximately 30° C. to 154° C.

Any temperature is included in the present invention so long as it isapplicable for the cooling after one-pot reaction. Additionally, manysimilar modifications in the art, substitutions to same object, ortemperature and temperature scope which are equivalent to thosedescribed in the invention, all are deemed to be included in the presentinvention. In some embodiments, the cooling temperature is approximatelyfrom −80° C. to 60° C. After the one-pot reaction is complete, thereaction mixture cooling is carried out at a higher temperature, may befrom solvent boiling point to 60° C., from solvent boiling point to 40°C., from solvent boiling point to 30° C., from solvent boiling point to25° C., from solvent boiling point to 0° C., from solvent boiling pointto −10° C., from solvent boiling point to −15° C., from solvent boilingpoint to −20° C., from solvent boiling point to −40° C., from solventboiling point to −50° C., or solvent boiling point to −80° C., and maybe from approximately 60° C. to −20° C., from approximately 50° C. to−20° C., from approximately 40° C. to 10° C., from approximately 30° C.to 10° C., or from approximately room temperature (usually 25° C.) to10° C. The reaction mixture cooling at the later stage is carried out ata lower temperature, may be from approximately −80° C. to approximately10° C., from approximately −60° C. to approximately 10° C., fromapproximately −40° C. to approximately 10° C., from approximately −20°C. to approximately 10° C., or from approximately −10° C. toapproximately 10° C., from approximately 0° C. to approximately 10° C.

Any temperature is included in the present invention so long as it canapplicable for the crystallization process of recrystallization.Additionally, many similar modifications in the art, substitutions tosame object, or temperature and temperature scope which are equivalentto those described in the invention, all are deemed to be included inthe present invention. In some embodiments, the crystallizationtemperature is approximately from −80° C. to 60° C. After all the crudeproduct is dissolved completely, the crystallization is at a highertemperature, may be from solvent boiling point to 60° C., from solventboiling point to 50° C., from solvent boiling point to 40° C., fromsolvent boiling point to 30° C., from solvent boiling point to 25° C.,from solvent boiling point to 0° C., from solvent boiling point to −10°C., from solvent boiling point to −15° C., from solvent boiling point to−20° C., from solvent boiling point to −30° C., from solvent boilingpoint to −40° C., from solvent boiling point to −50° C., or solventboiling point to −80° C., and may be from approximately 60° C. to −20°C., from approximately 50° C. to −20° C., from approximately 40° C. to10° C., from approximately 30° C. to 10° C., or from approximately roomtemperature (usually 25° C.) to 10° C. The crystallization at the laterstage is at a lower temperature, may be from approximately −80° C. toapproximately 10° C., from approximately −60° C. to approximately 10°C., from approximately −40° C. to approximately 10° C., fromapproximately −20° C. to approximately 10° C., from approximately −10°C. to approximately 10° C., or from approximately 0° C. to approximately10° C.

Any halogenating agent is included in the present invention so long asit is applicable for the halogenating reaction. For example,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide(NIS), 1,3-dibromo-5,5-dimethylhydantoin,1,3-dichloro-5,5-dimethylhydantoin, iodomethane, etc, or a combinationthereof.

The base used in the present invention may be an organic base orinorganic base. The organic base may be triethylamine, trimethylamine,N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine or acombination thereof; and can also be a base formed by reacting anorganic solvent with an alkali metal. The alkali metal compriseslithium, sodium and potassium, or a combination thereof. The organicsolvent can be one or more alcohols, or a combination thereof. Thealcohols include, but are not limited to, methanol, ethanol, propanol,i-propanol, n-butanol, i-butanol, tert-butanol and a combinationthereof. The inorganic bases include, but are not limited to, alkalimetal hydroxide, alkaline earth metal hydroxide, alkali metal alkoxide,alkaline earth metal alkoxide, alkali metal carbonate, alkaline earthmetal carbonate and ammonia. In some embodiments, the inorganic base isammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide,potassium hydroxide, lithium hydroxide, sodium carbonate, potassiumcarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxideor potassium tert-butoxide.

After the reaction proceeds to a certain extent in the presentinvention, such as the raw material is consumed more than 20%, more than30%, more than 40%, more than 50%, more than 70%, more than 80%, morethan 90%, more than 95%, or completely by monitoring, the reactionmixture is worked up, such as cooled, collected, drawn, filtered,separated, purified or a combination thereof. The reaction can bemonitored by conventional method such as thin-layer chromatography(TLC), high performance liquid chromatography (HPLC), gas chromatography(GC), and the like. The reaction mixture can be worked up byconventional method, for example, the crude product can be collected byconcentrating the reaction mixture through vacuum evaporation orconventional distillation and which is used directly in the nextoperation; or the crude product can be obtained by filtration of thereaction mixture and which is used directly in the next operation; orthe crude product can be get by pouring the supernatant liquid of thereaction mixture after standing for a while and which is used directlyin the next operation. And the reaction mixture can be purified bysuitable methods such as extraction, distillation, crystallization,column chromatography, washing, trituration with suitable organicsolvents or a combination thereof.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformeric)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, orgeometric (or conformeric) mixtures of the present compounds are withinthe scope disclosed herein.

Stereochemical definitions and conventions used herein generally followParker et al., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York and Eliel et al., Stereochemistry ofOrganic Compounds, John Wiley & Sons, Inc., New York, 1994. Thecompounds disclosed herein may contain asymmetric or chiral centers, andtherefore exist in different stereoisomeric forms. It is intended thatall stereoisomeric forms of the compounds disclosed herein, including,but not limited to, diastereomers, enantiomers and atropisomers, as wellas mixtures thereof such as racemic mixtures, form part of the presentinvention. Many organic compounds exist in optically active forms, i.e.,they have the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L, or R andS, are used to denote the absolute configuration of the molecule aboutits chiral center(s). The prefixes d and l or (+) and (−) are employedto designate the sign of rotation of plane-polarized light by thecompound, with (−) or l meaning that the compound is levorotatory. Acompound prefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer is referred to as anenantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The term “racemic mixture” or “racemate” refers to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.If tautomerism could happen (such as in a solvent), the chemical balancebetween tautomers can be reached. For example, proton tautomers (alsoknown as prototropic tautomers) include interconversions via migrationof a proton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons. The specific example of keto-enol tautomerisms ishexane-2,4-dione and 4-hydroxyhex-3-en-2-one tautomerism. Anotherexample of tautomerisms is phenol-keto tautomerism. The specific exampleof phenol-keto tautomerisms is pyridin-4-ol and pyridin-4(3H)-onetautomerism. Unless otherwise stated, all tautomers of the presentcompounds are within the scope disclosed herein.

General Synthetic Procedures

In the present invention, if the chemical name of the compound doesn'tmatch the corresponding structure, the compound is characterized by thecorresponding structure.

Generally, the compounds of Formula (I), Formula (Ia), Formula (I-1),Formula (Ia-1), Formula (I-2) or Formula (Ia-2) disclosed herein may beprepared by methods described herein, wherein the substituents are asdefined in Formula (I), Formula (Ia), Formula (I-1), Formula (Ia-1),Formula (I-2) or Formula (Ia-2), except where further noted. Thefollowing examples are presented to further exemplify the invention.

Persons skilled in the art will recognize that the chemical reactionsdescribed may be readily adapted to prepare a number of other compoundsdisclosed herein, and alternative methods for preparing the compoundsdisclosed herein are deemed to be within the scope disclosed herein. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, and/or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds disclosed herein.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius (° C.). Reagents werepurchased from commercial suppliers such as Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company, and were used withoutfurther purification unless otherwise indicated. Common solvents werepurchased from commercial suppliers such as Shantou XiLong ChemicalFactory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., GuangzhouReagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., QingdaoTenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

Column chromatography was conducted using a silica gel column. Silicagel (200-300 mesh) was purchased from Qingdao Ocean Chemical Factory. 1HNMR spectra were recorded by a Bruker Avance 400 MHz spectrometer orBruker Avance III HD 600 spectrometer, using CDCl₃, DMSO-d₆, CD₃OD oracetone-d₆ (reported in ppm) as solvent, and using TMS (0 ppm) orchloroform (7.25 ppm) as the reference standard. When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets), ddd (doublet of doubletof doublets), ddt (doublet of doublet of triplets), dddd (doublet ofdoublet of doublet of doublets), td (triplet of doublets), brs(broadened singlet). Coupling constants, when given, are reported inHertz (Hz).

Low-resolution mass spectral (MS) data were also determined on anAgilent 6320 series LC-MS spectrometer equipped with G1312A binarypumps, a G1316A TCC (Temperature Control of Column, maintained at 30°C.), a G1329A autosampler and a G1315B DAD detector were used in theanalysis. An ESI source was used on the LC-MS spectrometer.

Low-resolution mass spectral (MS) data were also determined on anAgilent 6120 series LC-MS spectrometer equipped with G1312A binarypumps, a G1316A TCC (Temperature Control of Column, maintained at 30°C.), a G1329A autosampler and a G1315B DAD detector were used in theanalysis. An ESI source was used on the LC-MS spectrometer.

Both LC-MS spectrometers were equipped with an Agilent Zorbax SB-C18,2.1×30 mm, 5 μm column. Injection volume was decided by the sampleconcentration. The flow rate was 0.6 mL/min. The HPLC peaks wererecorded by UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid inultrapure water (phase B). The gradient condition is shown in Table 1:

TABLE 1 The gradient condition of the mobile phase in Low-resolutionmass spectrum analysis Time A (CH₃CN, B (H₂O, (min) 0.1% HCOOH) 0.1%HCOOH) 0-3  5-100 95-0  3-6 100  0   6-6.1 100-5   0-95 6.1-8    5 95

Purities of compounds were assessed by Agilent 1100 Series highperformance liquid chromatography (HPLC) with UV detection at 210 nm and254 nm (Zorbax SB-C18, 2.1×30 mm, 4 micron, 10 min, 0.6 mL/min flowrate, 5 to 95% (0.1% formic acid in CH₃CN) in (0.1% formic acid in H₂O).Column was operated at 40° C.

The following abbreviations are used throughout the specification:

-   CDCl₃ chloroform-d-   DMF-d₆ N,N-dimethylformamide-d₆-   DMSO-d₆ dimethyl sulfoxide-d₆-   Acetone-d₆ acetone-d₆-   D₂O water-d₂-   EA, EtOAc ethyl acetate-   DMF N,N-dimethylformamide-   THF tetrahydrofuran-   NMP N-methylpyrrolidone-   MeCN, CH₃CN acetonitrile-   DCM, CH₂Cl₂ dichloromethane-   CHCl₃ chloroform-   CCl₄ tetrachloromethane-   PE petroleum ether-   CH₃OH, MeOH methanol-   g gram-   c concentration-   mol mole-   mmol millimole-   h hour, hours-   min minute, minutes-   mL milliliter-   v/v. v:v the ratio of volume-   DMSO dimethyl sulfoxide-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NIS N-iodosuccinimide

EXAMPLES

The preparation methods of optically pure dihydropyrimidine compoundsdisclosed in the examples of the present invention. Skilled in the artcan learn from this article to properly improve the process parametersto implement the preparation method. Of particular note is that allsimilar substitutions and modifications to the skilled person areobvious, and they are deemed to be included in the present invention.The methods disclosed herein were described in the preferred examples.Related person can clearly realize and apply the techniques disclosedherein by making some changes, appropriate alterations or combinationsto the methods without departing from spirit, principles and scope ofthe present disclosure.

In order to further understand the invention, it is detailed belowthrough examples.

Example Example 1: The Preparation of (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate

A flask was charged with (D)-ethyl 2-hydroxypropanoate (11.8 g, 10 mmol)and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (14.2 g, 10 mmol) in turn, andthen equipped with distillation apparatus or water segregator. Themixture was stirred at 120° C. for 4 hours. After the reaction, themixture was cooled and concentrated to obtain the title compound as puceliquid (12.9 g, 64%).

MS (ESI, pos.ion) m/z: 203.1 [M+H]⁺;

Step 2) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Method One:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2-bromo-4-fluorobenzaldehyde (20.3 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (74 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, themixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours.The resulting mixture was filtered. The filter cake was washed withwater (330 mL) and dried in vacuo at 60° C. for 8 hours to obtain thecrude product. To the crude product was added n-propanol (74 g). Themixture was heated until dissolved completely, cooled to 25° C., andthen kept at 25° C., stirred and crystallized for 5 hours. The resultingmixture was filtered. The filter cake was dried in vacuo at 60° C. for 8hours to obtain the product as a yellow solid (13.4 g, 27%).

[α]_(D) ²⁵=−122.46 (c=0.3054 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 497.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.02 (s, 1H), 7.97 (d, 1H), 7.89 (d, 1H),7.54 (dd, 1H), 7.36 (dd, 1H), 7.23 (td, 1H), 6.00 (s, 1H), 4.82 (q, 1H),4.14-4.01 (m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.13 (t, 3H).

The compound 5 can be prepared under the reaction conditions shown intable 2 by using method one described in step 2 of Example 1.

TABLE 2 The reaction conditions

(1):(2): The mass The mass (3):(4) ratio of ratio of Crystal- (mol); thereaction Reac- Cool- recrystal- ization amount solvent tion Reac- inglization on Quality; of com- to temper- tion temper- Cooling Recrystal-solvent temper- Crystal- yield (5) pound (1) Reaction compound aturetime ature time lization to com- ature lization of No. is 16.4 g solvent(1) (° C.) (h) (° C.) (h) solvent pound (1) (° C.) time (h) product 11:1:2:1 — — 78 12 40 6 ethanol 20 0 3 8.8 g; 17.8 2 1:1:1:1 ethanol 1 7812 40 8 ethanol 15 10 6 9.6 g; 19.4 3 1:1:1:1 ethanol 4.5 25 72 25 —ethanol 4.5 5 2 7.5 g; 15.2 4 1:1:1:1 ethanol 4.5 78 12 25 6 ethanol 325 1 12.9 g; 26.1 5 1:1:1:1 ethanol 20 60 24 −20 12 ethanol 4.5 25 610.1 g; 20.3 6 1:1:1:1 ethanol 80 78 12 −30 24 ethanol 5 25 4 7.5 g;15.1 7 1:1:1:1 DMF 4.5 154 1 −30 6 n-propanol 4 10 4 5.9 g; 11.9 81:1:1:1 n-butanol 5 100 5 0 6 n-butanol 4 25 6 11.2 g; 22.5 9 1:1:1:1n-propanol 4.5 80 12 25 6 n-propanol 3.5 40 10 12.4 g; 25.1 10 1:1:1:1i-propanol 4.5 82 12 25 1 i-propanol 5 25 4 9.6 g; 19.3 11 1:1:1:1t-butanol 4.5 82 12 30 12 i-propanol 4.5 25 6 10.6 g; 21.4 12 1:1:1:12-methoxy- 4.5 78 12 −10 12 t-propanol 5 25 4 10.1 g; ethanol 20.3 131:1:1:1 1,2-dimeth 4.5 78 12 −10 12 n-propanol 5 25 4 5.9 g; oxyethane11.8 14 1:1:1:1 ethyl 3 77 12 −10 12 t-propanol 4.5 25 4 7.6 g; acetate15.4 15 1:1:1:1 acetone 3 56 12 −20 12 t-propanol 5 25 4 4.2 g; 8.5 161:1:1:1 methanol 3 64 12 0 6 n-propanol 5 25 4 7.8 g; 15.8 17 1:1:1:12-methoxy- 5 78 6 −20 12 n-propanol 5 25 6 4.8 g; ethyl ether 9.7 181:1:1:1 ethanol 10 78 12 −20 12 ethanol 4.5 30 6 11.6 g; 23.3 19 1:1:1:1ethyl 3 77 12 −10 12 ethyl 2 −10 4 5.7 g; acetate acetate 11.4 201:1:1:1 ethanol 2 78 12 40 8 ethanol 15 10 6 9.9 g; 19.9 21 1:1:1:1ethanol 1 78 12 40 8 ethanol 10 10 6 10.3 g; 20.7Method Two:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2-bromo-4-fluorobenzaldehyde (20.3 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (74 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, thereaction mixture was cooled to 30° C., kept at 30° C. and stirred for 6hours. The mixture was filtered. The filtrate was washed with ethanol(50 g) and water (330 mL) in turn, and then dried in vacuo at 60° C. for8 hours to obtain the product as a yellow solid (14.4 g, 29%).

[a]_(D) ²⁵=122.46 (c=0.3054 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 497.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.02 (s, 1H), 7.97 (d, 1H), 7.89 (d, 1H),7.54 (dd, 1H), 7.36 (dd, 1H), 7.23 (td, 1H), 6.00 (s, 1H), 4.82 (q, 1H),4.14-4.01 (m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.13 (t, 3H).

The compound 5 can be prepared under the reaction conditions shown intable 3 by using method two described in step 2 of Example 1.

TABLE 3 The reaction conditions

(1):(2) The The (3):(4) mass mass (mol); ratio ratio the of of amountreac- Reac- Cool- wash- Wash- of com- tion tion Reac- ing Cool- ing ingQuality; pound solvent temper- tion temper- ing solvent temper- yield(1) is Reaction to com- ature time ature time Washing to com- ature (%)of No. 16.4 g solvent pound (1) (° C.) (h) (° C.) (h) solvent pound (1)(° C.) product 1 1:1:2:1 — — 78 12 40 6 ethanol 15 25 9.5 g; 19.2 21:1:1:1 ethanol 1 78 12 40 6 ethanol 10 25 10.3 g; 20.8 3 1:1:1:1ethanol 4.5 25 72 25 — ethanol 3 25 8.5 g; 17.1 4 1:1:1:1 ethanol 4.5 7812 25 6 ethanol 3.5 25 13.7 g; 27.6 5 1:1:1:1 ethanol 20 60 24 −10 6ethanol 4.5 25 11.1 g; 22.4 6 1:1:1:1 ethanol 80 78 12 −30 12 ethanol 525 8.4 g; 16.9 7 1:1:1:1 ethanol 8 78 12 25 6 — — — 13.1 g; 26.5 81:1:1:1 DMF 4.5 154 1 −30 6 ethanol 4 25 6.6 g; 13.3 9 1:1:1:1 n-butanol5 100 5 0 6 n-butanol 2 25 12.3 g; 24.7 10 1:1:1:1 n-propanol 4.5 80 1225 6 n-propanol 3 25 14.2 g; 28.6 11 1:1:1:1 i-propanol 4.5 82 12 25 1t-propanol 3 25 10.7 g; 21.5 12 1:1:1:1 t-butanol 4.5 82 12 30 12t-butanol 3 30 11.7 g; 23.6 13 1:1:1:1 2-methoxy 4.5 78 12 −10 122-methoxy- 1 0 10.9 g; ethanol ethanol 21.9 14 1:1:1:1 1,2-dimeth 4.5 7812 −10 12 n-propanol 3 25 6.6 g; oxyethane 13.4 15 1:1:1:1 ethyl 3 77 12−10 12 i-propanol 3.5 25 8.33 g; acetate 16.8 16 1:1:1:1 acetone 3 56 12−20 12 t-propanol 3 25 5.3 g; 10.6 17 1:1:1:1 methanol 3 64 12 0 6n-propanol 2 25 8.8 g; 17.7 18 1:1:1:1 2-methoxy 5 78 6 −20 12n-propanol 2 25 5.6 g; ethyl ether 11.3 19 1:1:1:1 n-propanol 4.5 80 1225 6 t-propanol 20 0 10.4 g; 20.9Method Three:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2-bromo-4-fluorobenzaldehyde (20.3 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (74 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, themixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours.The resulting mixture was filtered. The filter cake was washed withwater (330 mL) and dried in vacuo at 60° C. for 8 hours to obtain thecrude product. The crude product was triturated with n-propanol (50 g)at 30° C. for 5 hours and filtered. The filter cake was washed withn-propanol (12.8 g) and dried in vacuo at 60° C. for 8 hours to obtainthe product as a yellow solid (13.9 g, 28%).

[α]_(D) ²⁵=122.46 (c=0.3054 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 497.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.02 (s, 1H), 7.97 (d, 1H), 7.89 (d, 1H),7.54 (dd, 1H), 7.36 (dd, 1H), 7.23 (td, 1H), 6.00 (s, 1H), 4.82 (q, 1H),4.14-4.01 (m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.13 (t, 3H).

The compound 5 can be prepared under the reaction conditions shown intable 4 by using method three described in step 2 of Example 1.

TABLE 4 The reaction conditions

The (1):(2) The mass (3):(4) mass ratio (mol); ratio of the of tritu-amount reac- Reac- Cool- ration Tritu- Tritu- of com- tion tion Reac-ing Cool- solvent ration ration Quality; pound solvent temper- tiontemper- ing Tritu- to com- temper- on yield (1) is Reaction to com-ature time ature time ration pound ature time (%) of No. 16.4 g solventpound (1) (° C.) (h) (° C.) (h) solvent (1) (° C.) (h) product 1 1:1:2:1— — 78 12 40 6 ethanol 13 25 10 9.2 g; 18.6 2 1:1:1:1 ethanol 1 78 12 406 ethanol 9 25 5 10 g; 20.2 3 1:1:1:1 ethanol 4.5 25 72 25 — ethanol 325 4 8.2 g; 16.5 4 1:1:1:1 ethanol 4.5 78 12 25 6 ethanol 6 5 2 13.3 g;26.8 5 1:1:1:1 ethanol 20 60 24 −20 12 ethanol 4 25 1 10.7 g; 21.5 61:1:1:1 ethanol 80 78 12 −30 24 ethanol 4 25 5 7.9 g; 15.9 7 1:1:1:1 DMF4.5 154 1 −30 6 n-propanol 3.5 25 6 6.3 g; 12.7 8 1:1:1:1 n-butanol 5100 5 0 6 n-butanol 3.5 25 4 11.6 g; 23.4 9 1:1:1:1 n-propanol 4.5 80 1225 6 n-propanol 3 40 8 13.7 g; 27.7 10 1:1:1:1 i-propanol 4.5 82 12 25 1i-propanol 4 25 3 10.1 g; 20.4 11 1:1:1:1 t-butanol 4.5 82 12 30 12i-propanol 4 30 5 11.2 g; 22.5 12 1:1:1:1 2-methoxy 4.5 78 12 −10 12i-propanol 4 25 5 10.5 g; ethanol 21.1 13 1:1:1:1 1,2-dimeth- 4.5 78 12−10 12 n-propanol 3.5 25 3 6.3 g; oxyethane 12.7 14 1:1:1:1 ethyl 3 7712 −10 12 i-propanol 4 25 4 8 g; acetate 16.2 15 1:1:1:1 acetone 3 56 12−20 12 i-propanol 4 25 6 4.7 g; 9.4 16 1:1:1:1 methanol 3 64 12 0 6n-propanol 3.5 25 3 8.2 g; 16.5 17 1:1:1:1 2-methoxy 5 78 6 −20 12n-propanol 3.5 25 3 5.3 g; ethyl 10.6 ether 18 1:1:1:1 ethanol 1 78 1240 6 ethanol 10 25 5 9.4 g; 18.8 19 1:1:1:1 i-propanol 4.5 82 12 25 1i-propanol 20 5 3 8.9 g; 17.9 20 1:1:1:1 ethyl 3 77 12 −10 12 ethyl 2−10 12 6.7 g; acetate acetate 13.5 21 1:1:2:1 — — 78 12 40 6 ethanol 1525 10 9.0 g; 18.1

Step 3) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(49.6 g, 0.1 mol) and tetrachloromethane (1000 g). The mixture washeated at 76° C., NBS was added (19.6 g, 0.11 mol), and then thereaction mixture was stirred for 30 min. After the reaction, thereaction mixture was cooled and concentrated. To the residue was addedethanol (250 g). The resulting mixture was cooled to 0° C., kept at 0°C. and stirred. After the solid precipitated out completely, the mixturewas filtered. The filter cake was washed with ethanol (50 g) and driedin vacuo at 60° C. for 6 hours to obtain the product as a yellow solid(37.4 g, 65%).

MS (ESI, pos.ion) m/z: 575.8 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 8.03 (d, 1H), 7.98 (br, 1H), 7.58 (dd, 2H),7.43 (dd, 1H), 7.27 (td, 1H), 6.01 (s, 1H), 4.94 (q, 1H), 4.85 (br, 2H),4.14-4.02 (m, 2H), 1.28 (d, 3H), 1.16 (t, 3H).

The compound A1 can be prepared under the reaction conditions shown intable 5 according to the procedure described in step 3 of Example 1

TABLE 5 The reaction conditions

Compound The (5):NBS The mass mass ratio (mol) the ratio of of theamount of reaction The additional Quality; compound solvent to Reactionsolvent solvent to yield (5) is Reaction compound temperature added tocompound (%) of No. 49.6 solvent (5) (° C.) the residue (5) product 11:1.1, DCM 30 39 i-propanol 7 41.4 g; 72 2 1:1.05, DCM 10 39 ethanol 538 g; 66 3 1:1.15, CHCl₃ 20 61 n-propanol 6 42 g; 73 4 1:1.1, CCl₄ 20 76ethanol 5 43.1 g; 75

Step 4) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(57.5 g, 0.1 mol), i-propanol (287 g) and morpholine (34.8 g, 0.4 mol).The mixture was stirred at 55° C. for 4 hours. After the reaction, themixture was cooled to 0° C., kept at this temperature and stirred. Afterthe solid precipitated out completely, the mixture was filtered. Thefilter cake was washed with i-propanol (58 g) followed by water (575 g),and then dried in vacuo at 60° C. for 8 hours to obtain the product as ayellowish solid (40.1 g, 69%).

MS (ESI, pos.ion) m/z: 581.2 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.98 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H),7.56 (d, 1H), 7.42 (dd, 1H), 7.23 (td, 1H), 6.05 (s, 1H), 4.84 (q, 1H),4.14-4.05 (m, 2H), 3.92 (dd, 2H), 3.67 (br, 4H), 2.55 (br, 4H), 1.23 (d,3H), 1.16 (t, 3H).

Step 5) (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (435 g) and lithium (1.74 g,0.25 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then a solution of(R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(58.1 g, 0.1 mol) in ethanol (435 g) was added. The reaction mixture wasstirred at 78° C. for 1.5 hours. After the reaction, the reactionmixture was cooled and concentrated. To the residue was added ethylacetate (580 g). The mixture was washed with water (250 g×2). Thecombined organic layers were concentrated to obtain the product as ayellow solid (39.7 g, 78%).

MS (ESI, pos.ion) m/z: 509.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H),7.57 (dd, 1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.05 (s, 1H), 3.96 (q, 2H),3.93 (dd, 2H), 3.68 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).

Example 2: The Preparation of (R)-methyl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous methanol (870 g) and lithium (1.74 g,0.25 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(58.1 g, 0.1 mol) was added. The reaction mixture was allowed to warm upto 60° C. and stirred for 1.5 hours. After the reaction, the reactionmixture was cooled and concentrated. To the residue was added ethylacetate (580 g). The mixture was washed with water (250 g×2). Thecombined organic layers were concentrated to obtain the product asyellow thick oil (36.1 g, 73%).

MS (ESI, pos.ion) m/z: 494.7 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.71 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H),7.55 (dd, 1H), 7.37 (dd, 1H), 7.20 (td, 1H), 6.02 (s, 1H), 3.91 (dd,2H), 3.67 (br, 4H), 3.52 (s, 3H), 2.55 (br, 4H).

Example 3: The Preparation of (R)-3-(morpholin-3-yl)propanoic acidhydrochloride

Step 1) (S)-tert-butyl 3-formylmorpholine-4-carboxylate

To a flask were added (R)-tert-butyl3-(hydroxymethyl)morpholine-4-carboxylate (1.47 g, 6.77 mmol) and DCM(30 mL) in turn, and then Dess-Martin periodinane (3.44 g, 8.12 mmol)was added at 0° C. The mixture was stirred at 0° C. for 1 hour. Afterthe reaction, the mixture was quenched with saturated aqueous sodiumbicarbonate (30 mL) and separated. The organic layer was washed withsaturated aqueous sodium bicarbonate (30 mL×3) and saturated aqueoussodium chloride (30 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was used directly at next operation.

Step 2) (R)-tert-butyl3-(3-ethoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate

To a flask were added (S)-tert-butyl 3-formylmorpholine-4-carboxylate(1.46 g, 6.77 mmol), DCM (40 mL) and ethyl(triphenylphosphoranylidene)acetate (2.36 g, 6.77 mmol) in turn. Themixture was stirred at 25° C. for 12 hours. After the reaction, themixture was filtered. The filtrate was concentrated. The residue waspurified by silica gel chromatography eluted with PE/EtOAc (V/V)=10/1 togive the product as a colorless oil (1.05 g, 54%).

MS (ESI, pos.ion) m/z: 186.1 [M+H-100]⁺;

¹H NMR (400 MHz, CDCl₃): δ 6.69 (dd, 1H), 5.89 (dd, 1H), 4.56 (s, 1H),4.20-4.12 (m, 2H), 3.94-3.82 (m, 2H), 3.77-3.65 (m, 2H), 3.53-3.43 (m,1H), 3.27-3.10 (m, 1H), 1.41 (s, 9H), 1.29-1.23 (m, 3H).

Step 3) (R)-tert-butyl 3-(3-ethoxy-3-oxopropyl)morpholine-4-carboxylate

To a flask were added (R)-tert-butyl3-(3-ethoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate (1.05 g, 3.68mmol), anhydrous ethanol (20 mL) and Pd—C (10%, 0.2 g) in turn. Themixture was stirred at 30° C. under hydrogen atmosphere overnight andfiltered. The filtrate was concentrated to give the product as colorlessoil (0.96 g, 91%).

MS (ESI, pos.ion) m/z: 188.1 [M+H-100]⁺;

¹H NMR (400 MHz, CDCl₃): δ 4.12 (q, 2H), 3.98 (s, 1H), 3.84-3.69 (m,3H), 3.56 (dd, 1H), 3.42 (td, 1H), 3.12 (t, 1H), 2.37-2.27 (m, 2H),2.25-2.15 (m, 1H), 1.92-1.83 (m, 1H), 1.45 (s, 9H), 1.25 (t, 3H).

Step 4) (R)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)propanoic acid

To a flask were added (R)-tert-butyl3-(3-ethoxy-3-oxopropyl)morpholine-4-carboxylate (0.96 g, 3.34 mmol),anhydrous ethanol (10 mL) and a solution of lithium hydroxide hydrate(1.4 g, 33.4 mmol) in water (10 mL) in turn. The mixture was stirred at25° C. for 30 min. After the reaction, to the reaction mixture was addedethyl acetate (150 mL) and water (50 mL). The resulting mixture wasadjusted to pH 5-6 with concentrated hydrochloric acid at 0° C. Afterthe mixture was partitioned. The organic layer was washed with saturatedaqueous sodium chloride (100 mL), dried over anhydrous sodium sulfateand concentrated to give the product as colorless oil (0.85 g, 98%).

MS (ESI, pos.ion) m/z: 160.1 [M+H-100]⁺;

¹H NMR (400 MHz, CDCl₃): δ 8.08 (br, 1H), 4.03 (brs, 1H), 3.88-3.72 (m,3H), 3.58 (dd, 1H), 3.44 (td, 1H), 3.13 (t, 1H), 2.43-2.29 (m, 2H),2.27-2.20 (m, 1H), 1.94-1.83 (m, 1H), 1.46 (s, 9H).

Step 5) (R)-3-(morpholin-3-yl)propanoic acid hydrochloride

To a flask were added(R)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)propanoic acid (0.9 g, 3.47mmol) and a solution of hydrogen chloride in ethyl acetate (4 mol/L, 15mL) in turn. The mixture was stirred at 25° C. for 4 hours. After thereaction, the mixture was filtered to give the product as a white solid(0.53 g, 78%).

MS (ESI, pos.ion) m/z: 160.1 [M+H]⁺;

¹H NMR (400 MHz, D₂O): δ 4.04-3.96 (m, 2H), 3.75-3.68 (m, 1H), 3.52 (dd,1H), 3.40-3.35 (m, 1H), 3.34-3.29 (m, 1H), 3.22-3.15 (m, 1H), 2.47 (t,2H), 1.83 (ddd, 2H).

The compound VI hydrochloride can be prepared under the reactionconditions shown in table 6 according to the procedure described inExample 3.

TABLE 6 The reaction conditions for preparation of the compound (VI)hydrochloride Raw material The amount of raw material

Product character Quality; yield (%) of product

50 g

white solid   23 g; 51

50 g

white solid 21.2 g; 47

50 g

white solid 18.5 g; 41

50 g

white solid 17.8 g; 39

50 g

gray solid 16.4 g; 36

50 g

gray solid 17.3 g; 38

TABLE 6-1 The NMR and MS datum of the compound (VI) hydrochloride

NMR MS

¹H NMR (400 MHz, D₂O): δ 4.03 (dd, 1H), 3.78-3.67 (m, 2H), 3.25 (t, 2H),3.08 (td, 1H), 2.85 (dd, 1H), 2.27-2.23 (m, 2H), 1.73-1.67 (m, 2H). MS(ESI, neg. ion) m/z: 158.2[M − H]⁻

¹H NMR (400 MHz, D₂O): δ 4.10-4.02 (m, 1H), 3.80-3.74 (m, 2H), 3.32-3.25(m, 2H), 3.10 (td, 1H), 2.89 (t, 1H), 2.47-2.43 (m, 2H), 1.88-1.70 (m,2H). MS (ESI, pos. ion) m/z: 160.1 [M + H]⁺;

¹H NMR (400 MHz, D₂O): δ 4.07-3.98 (m, 2H), 3.78-3.71 (m, 1H), 3.55 (dd,1H), 3.43-3.38 (m, 1H), 3.35 (dt, 1H), 3.24-3.17 (m, 1H), 2.50 (t, 2H),1.89-1.83 (m, 2H). MS (ESI, pos. ion) m/z: 160.3 [M + H]⁺;

¹H NMR (600 MHz, D₂O): δ 4.05 (dd, 1H), 3.84-3.79 (m, 1H), 3.74-3.70 (m,1H), 3.34 (d, 1H), 3.21 (td, 1H), 3.10 (td, 1H), 2.55 (t, 2H), 2.06-2.03(m, 1H), 1.82-1.76 (m, 1H), 1.26 (d, 3H). MS (ESI, pos. ion) m/z: 174.3[M + H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.21 (br, 1H), 3.80-3.73 (m, 2H),3.66-3.59 (m, 1H), 2.74-2.67 (m, 1H), 2.43-2.40 (m, 2H), 2.33-2.23 (m,1H), 2.05-1.95 (m, 2H). MS (ESI, pos. ion) m/z: 180.2 [M + H]⁺;

¹H NMR (600 MHz, D₂O): δ 4.00-3.94 (m, 1H), 3.82 (dd, 1H), 3.72 (dd,1H), 2.83-2.76 (m, 1H), 2.57-2.47 (m, 2H), 2.39-2.32 (m, 1H), 2.16-2.03(m, 2H). MS (ESI, pos. ion) m/z: 180.2 [M + H]⁺;

Example 4: The Preparation of (2R,3S)-2-methylmorpholine-3-carboxylicacid)

The title compound ((2R,3S)-2-methylmorpholine-3-carboxylic acid) wasprepared according to the procedure described in example 34 of patentWO2014029193.

MS (ESI, pos.ion) m/z: 146.2 [M+H]⁺;

¹H NMR (600 MHz, D₂O): δ 4.01-3.98 (m, 1H), 3.82-3.77 (m, 1H), 3.76-3.72(m, 1H), 3.37 (d, 1H), 3.27-3.24 (m, 1H), 3.19-3.14 (m, 1H), 1.26 (d,3H).

Example 5: The Preparation of(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

Step 1)(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-((((R)-1-ethoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(57.5 g, 0.1 mol), ethanol (840 g), (S)-morpholine-3-carboxylic acid(13.1 g, 0.1 mol) and potassium carbonate (27.6 g, 0.2 mol) in turn. Themixture was stirred at 30° C. under nitrogen atmosphere for 12 hours.After the reaction, the mixture was filtered. The filtrate wasconcentrated. To the residue was added water (840 g), the resultingmixture was extracted with ethyl acetate (840 mL). The organic layer wasdiscarded. To the aqueous layer was added ethyl acetate (900 mL), andthe mixture was adjusted to pH 3-6 with concentrated hydrochloric acid.The organic layer was dried over anhydrous sodium sulfate andconcentrated to give the product as a yellow solid (46.3 g, 74%).

MS (ESI, pos.ion) m/z: 624.5 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 8.03 (d, 1H), 7.94 (d, 1H), 7.56 (dd, 1H),7.42 (dd, 1H), 7.22 (td, 1H), 6.06 (s, 1H), 4.84 (q, 1H), 4.23-4.13 (m,1H), 4.12-4.03 (m, 3H), 3.98-3.88 (m, 1H), 3.85 (dd, 1H), 3.73-3.65 (m,2H), 3.58-3.51 (m, 1H), 3.10-3.04 (m, 1H), 2.42-2.38 (m, 1H), 1.24 (d,3H), 1.13 (t, 3H).

The compound E can be prepared under the reaction conditions shown intable 7 according to the procedure described in step 1 of Example 5.

TABLE 7 The reaction conditions for preparation of compound E

No.

CompoundA1: compound(VI) (mol) the amount of compound A1 is 5.75 gReaction solvent Reaction temperature(° C.) Reaction time(h) Productcharacter Quality; yield (%) of product E1

1:1 ethanol 30 12 yellow solid 4.58 g; 70 E2

1:1 ethanol 30 12 yellow solid 4.32 g; 66 E3

1:1 ethanol 30 12 yellow solid  3.2 g; 49 E4

1:1 ethanol 30 12 yellow solid 5.11 g; 80 E5

1:1 ethanol 30 12 yellow solid 3.41 g; 51 E6

1:1 ethanol 30 12 yellow solid 4.58 g; 71 E7

1:1 ethanol 30 12 yellow solid  3.5 g; 52 E8

1:1 ethanol 30 12 yellow solid  3.3 g; 49

TABLE 7-1 The NMR and MS datum of compound E No. ¹H NMR MS E1 ¹H NMR(600 MHz, DMSO-d₆): δ 12.02 (br, 1H), 9.74 (s, 1H), 8.02 MS (ESI,pos.ion) (d, 1H), 7.95 (d, 1H), 7.56 (dd, 1H), 7.40 (dd, 1H), 7.22 (td,1H), 6.06 m/z: 652.5 (s, 1H), 4.85 (q, 1H), 4.12-4.05 (m, 2H), 3.92-3.85(m, 3H), 3.59-3.55 [M + H]⁺; (m, 1H), 3.52-3.48 (m, 1H), 2.79 (t, 2H),2.35-2.23 (m, 3H), 2.02 (t, 1H), 1.65-1.61 (m, 2H), 1.24 (d, 3H), 1.14(t, 3H). E2 ¹H NMR (600 MHz, DMSO-d₆): δ 12.06 (br, 1H), 9.76 (s, 1H),8.04 MS (ESI, pos.ion) (d, 1H), 7.96 (d, 1H), 7.56 (dd, 1H), 7.40 (dd,1H), 7.23 (td, 1H), 6.04 m/z: 652.5 (s, 1H), 4.86 (q, 1H), 4.14-4.06 (m,2H), 3.94-3.86 (m, 3H), 3.58-3.53 [M + H]⁺; (m, 1H), 3.51-3.48 (m, 1H),2.77 (t, 2H), 2.35-2.22 (m, 3H), 2.01 (t, 1H), 1.65-1.62 (m, 2H), 1.25(d, 3H), 1.12 (t, 3H). E3 ¹H NMR (600 MHz, DMSO-d₆): δ 12.16 (s, 1H),9.91 (s, 1H), 8.03 MS (ESI, pos.ion) (d, 1H), 7.94 (d, 1H), 7.55 (dd,1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.05 m/z: 653.2 (s, 1H), 4.85 (q,1H), 4.18 (d, 1H), 4.13-4.01 (m, 2H), 3.86 (d, 1H), 3.80 [M + H]⁺; (d,1H), 3.73-3.71 (m, 1H), 3.62-3.55 (m, 1H), 3.36-3.33 (m, 1H), 2.94-2.73(m, 1H), 2.56-2.53 (m, 1H), 2.39-2.31 (m, 1H), 2.28-2.22 (m, 1H),1.88-1.82 (m, 1H), 1.66-1.58 (m, 1H), 1.25 (d, 3H), 1.13 (t, 3H). E4 ¹HNMR (600 MHz, DMSO-d₆): δ 12.98 (br, 1H), 9.90 (s, 1H), 8.04 MS (ESI,pos.ion) (d, 1H), 7.94 (d, 1H), 7.56 (dd, 1H), 7.43 (dd, 1H), 7.21 (td,1H), 6.04 m/z: 639.1 (s, 1H), 4.86 (q, 1H), 4.14-4.03 (m, 3H), 3.93-3.85(m, 1H), 3.74-3.67 [M + H]⁺; (m, 2H), 3.65-3.60 (m, 1H), 3.01 (d, 1H),2.92 (d, 1H), 2.49-2.44 (m, 1H), 1.23 (d, 3H), 1.21 (d, 3H), 1.13 (t,3H). E5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.10 (s, 1H), 9.75 (s, 1H), 8.04MS (ESI, pos.ion) (d, 1H), 7.96 (d, 1H), 7.56 (dd, 1H), 7.40 (dd, 1H),7.20 (td, 1H), 6.05 m/z: 668.6 (s, 1H), 4.87 (q, 1H), 4.15 (d, 1H),4.11-4.02 (m, 2H), 3.85 (d, 1H), [M + H]⁺; 3.76-3.71 (m, 1H), 3.60-3.55(m, 1H), 3.53-3.46 (m, 1H), 2.66 (d,1H),2.46-2.41 (m,1H), 2.37-2.32(m,3H), 2.07-1.87 (m,1H), 1.79-1.72 (m, 1H), 1.24 (d, 3H), 1.20 (d, 3H),1.14 (t, 3H). E6 ¹H NMR (600 MHz, DMSO-d₆): δ 13.05 (br, 1H), 9.79 (s,1H), 7.98 MS (ESI, pos.ion) (d, 1H), 7.92 (d, 1H), 7.57 (dd, 1H), 7.43(dd, 1H), 7.23 (td, 1H), 6.04 m/z: 644.5 (s, 1H), 4.85 (q, 1H), 4.31 (d,1H), 4.13-4.05 (m, 3H), 3.92 (t, 1H), [M + H]⁺; 3.55-3.49 (m, 1H),3.18-3.12 (m, 1H), 2.82-2.72 (m, 1H), 2.48-2.43 (m, 1H), 1.24 (d, 3H),1.16 (t, 3H). E7 ¹H NMR (600 MHz, DMSO-d₆): δ 9.56 (s, 1H), 8.04 (d,1H), 7.96(d, MS (ESI, pos.ion) 1H), 7.57 (d, 1H), 7.43 (dd, 1H),7.24(td,1H), 6.04 (s, 1H), 4.86 (q, 1H), m/z: 673.1 4.12-4.03 (m, 4H),3.51-3.44 (m, 1H), 3.08-2.94 (m, 2H), 2.48-2.44 (m, [M + H]⁺; 1H),2.37-2.19 (m, 2H), 2.13-2.01 (m, 1H), 1.98-1.91(m, 1H), 1.58-1.52 (m,1H), 1.24 (d, 3H), 1.16 (t, 3H). E8 ¹H NMR (600 MHz, DMSO-d₆): δ 9.52(br, 1H), 9.79 (s, 1H), 8.02 MS (ESI, pos.ion) (d, 1H), 7.94 (d, 1H),7.56 (dd, 1H), 7.40 (dd, 1H), 7.23 (td, 1H), 6.03 m/z: 672.7 (s, 1H),4.87 (q, 1H), 4.14 (d, 1H), 3.47-3.42 (m, 3H), 3.02 (t, 1H), [M + H]⁺;2.60-2.52 (m, 1H), 2.41-2.21 (m, 1H), 2.12-1.98 (m, 1H), 1.61-1.59 (m,1H), 1.24 (d, 3H), 1.14 (t, 3H).

Step 2)(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added anhydrous ethanol (940 g) and lithium (2.43 g,0.35 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-((((R)-1-ethoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid (62.5 g, 0.1 mol) was added. The reaction mixture was allowed towarm up to 78° C. and stirred for 12 hours. After the reaction, themixture was cooled and concentrated. To the residue was added water(1200 g), the resulting mixture was extracted with ethyl acetate (1000mL). The organic layer was discarded. To the aqueous layer was addedethyl acetate (1280 mL), the mixture was adjusted to pH 3-6 withconcentrated hydrochloric acid. The organic layer was dried overanhydrous sodium sulfate and concentrated to give the product as ayellow solid (37.1 g, 67%).

MS (ESI, pos.ion) m/z: 553.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 12.85 (br, 1H), 9.80 (s, 1H), 8.00 (d, 1H),7.91 (d, 1H), 7.54 (dd, 1H), 7.39 (dd, 1H), 7.19 (td, 1H), 6.01 (s, 1H),4.25 (d, 1H), 4.02 (d, 1H), 3.97-3.91 (m, 3H), 3.81 (dd, 1H), 3.72-3.69(m, 1H), 3.66-3.63 (m, 1H), 3.61-3.58 (m, 1H), 3.10-3.03 (m, 1H),2.42-2.35 (m, 1H), 1.04 (t, 3H).

The compound F can be prepared under the reaction conditions shown intable 8 according to the procedure described in step 2 of Example 5.

TABLE 8 The reaction conditions for preparation of compound F

No. R³

The mole ratio of Lithium to compound E; the amount of compound EReaction solvent Reaction temperature(° C.) Reaction time(h) Productcharacter Quality; yield (%) of product F1 ethyl

6; 6.4 g ethanol 78 2 yellow solid 3.78 g; 65 F2 ethyl

5; 6.4 g ethanol 78 2 yellow solid 3.66 g; 63 F3 ethyl

5; 6.4 g ethanol 78 2 yellow solid 3.02 g; 52 F4 ethyl

5; 6.26 g  ethanol 78 12 yellow solid 3.97 g; 70 F5 ethyl

5; 6.54 g  ethanol 78 2 yellow solid 2.86 g; 48 F6 ethyl

5; 6.3 g ethanol 78 12 yellow solid  3.5 g; 61 F7 ethyl

5; 6.6 g ethanol 78 2 yellow solid 3.13 g; 52 F8 ethyl

5; 6.6 g ethanol 78 2 yellow solid   3 g; 50 F9 methyl

2; 6.1 g methanol 64 18 yellow solid 3.61 g; 67 F10 methyl

5; 6.4 g methanol 64 6 yellow solid 3.52 g; 62 F11 methyl

5; 6.4 g methanol 64 4 yellow solid  3.4 g; 60 F12 methyl

5; 6.4 g methanol 64 8 yellow solid 2.72 g; 48 F13 methyl

5; 6.26 g  methanol 64 18 yellow solid 3.87 g; 70 F14 methyl

5; 6.54 g  methanol 64 5 yellow solid 2.73 g; 47 F15 methyl

5; 6.3 g methanol 64 12 yellow solid 3.75 g; 67 F16 methyl

5; 6.87 g  methanol 64 6 yellow solid 2.88 g; 49 F17 methyl

5; 6.87 g  methanol 64 6 yellow solid 2.82 g; 48

TABLE 8-1 The NMR and MS datum of compound F No. ¹H NMR MS F1 ¹H NMR(400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.65 (s, 1H), 8.02 (d, 1H), MS(ESI, pos.ion) 7.94 (d, 1H), 7.57 (dd, 1H), 7.39 (dd, 1H), 7.22 (td,1H), 6.03 (s, 1H), 3.96 m/z: 581.2 (q, 2H), 3.89-3.85 (m, 3H), 3.61-3.47(m, 2H), 2.81-2.75 (m, 2H), 2.38-2.21 [M + H]⁺; (m, 3H), 2.04-2.02 (m,1H), 1.65-1.60 (m, 2H), 1.06 (t, 3H). F2 ¹H NMR (400 MHz, DMSO-d₆): δ12.06 (s, 1H), 9.66 (s, 1H), 8.02 (d, 1H), MS (ESI, pos.ion) 7.95 (d,1H), 7.56 (dd, 1H), 7.41 (dd, 1H), 7.20 (td, 1H), 6.03 (s, 1H), 3.97m/z: 580.9 (q, 2H), 3.93-3.83 (m, 3H), 3.57-3.46 (m, 2H), 2.88 (d, 1H),2.63 (d, 1H), [M + H]⁺; 2.37-2.22 (m, 3H), 2.13-2.08 (m, 1H), 1.75-1.65(m, 2H), 1.06 (t, 3H). F3 ¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (br, 1H),9.82 (s, 1H), 8.02 MS (ESI, pos.ion) (d, 1H), 7.92 (d, 1H), 7.54 (dd,1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.03 m/z: 580.9 (s, 1H), 4.18 (d,1H), 3.96 (q, 2H), 3.91 (d, 1H), 3.82-3.79 (m, 1H), [M + H]⁺; 3.74-3.71(m, 1H), 3.61-3.57 (m, 1H), 3.37-3.32 (m, 1H), 2.78-2.75 (m, 1H),2.57-2.53 (m, 1H), 2.49-2.47 (m, 1H), 2.38-2.32 (m, 2H), 1.89-1.84 (m,1H), 1.68-1.58 (m, 1H), 1.06 (t, 3H). F4 ¹H NMR (400 MHz, DMSO-d₆): δ13.02 (s, 1H), 9.78 (s, 1H), 8.03 (d, 1H), MS (ESI, pos.ion) 7.93 (d,1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.22 (td, 1H), 6.00 (s, 1H), 4.10m/z: 567.1 (d, 1H), 3.95 (q, 2H), 3.90-3.87 (m, 1H), 3.76-3.60 (m, 3H),3.46-3.42 [M + H]⁺; (m, 1H), 2.98 (d, 1H), 2.93 (d, 1H), 1.21 (d, 3H),1.05 (t, 3H). F5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.74 (s,1H), 8.02 (d, 1H), MS (ESI, pos.ion) 7.95 (d, 1H), 7.56 (dd, 1H), 7.39(dd, 1H), 7.19 (td, 1H), 6.04 (s, 1H), 4.16 m/z: 594.6 (d, 1H),4.00-3.93 (m, 2H), 3.86 (d, 1H), 3.77-3.72 (m, 1H), 3.59-3.53 [M + H]⁺(m, 1H), 3.51-3.45 (m, 1H), 2.66 (d, 1H), 2.46-2.40 (m, 1H), 2.37-2.30(m, 3H), 2.03 -1.91 (m, 1H), 1.80-1.73 (m, 1H), 1.20 (d, 3H), 1.06 (t,3H). F6 ¹H NMR (600 MHz, DMSO-d₆): δ 9.98 (br, 1H), 8.03 (d, 1H), 8.00(d, 1H), MS (ESI, pos.ion) 7.61 (dd, 1H), 7.48 (dd, 1H), 7.28 (td, 1H),6.02 (s, 1H), 4.35 (d, 1H), 4.13 m/z: 573.0 (d, 1H), 4.01-3.94 (m, 3H),3.61-3.51 (m, 1H), 3.25-3.19 (m, 1H), 3.10-3.04 [M + H]⁺; (m, 1H),2.86-2.68 (m, 1H), 1.20 (t, 3H). F7 ¹H NMR (600 MHz, DMSO-d₆): δ 12.08(s, 1H), 9.51 (s, 1H), 8.01 (d, 1H), MS (ESI, pos.ion) 7.93 (d, 1H),7.57 (dd, 1H), 7.41 (dd, 1H), 7.24 (td, 1H), 6.01 (s, 1H), 4.12 m/z:601.1 (dd, 2H), 3.97 (q, 2H), 3.61-3.52 (m, 1H), 3.04-2.96 (m, 2H),2.58-2.56 [M + H]⁺; (m, 1H), 2.35-2.20 (m, 2H), 2.12-1.98 (m, 1H),1.93-1.90 (m, 1H), 1.56-1.48 (m, 1H), 1.06 (t, 3H). F8 ¹H NMR (400 MHz,CDCl₃): δ 12.19 (br, 1H), 9.46 (s, 1H), 7.86 (d, 1H), MS (ESI, pos.ion)7.50 (d, 1H), 7.37-7.33 (m, 2H), 7.00 (td, 1H), 6.19 (s, 1H), 4.52 (d,1H), m/z: 601.2 4.14-4.03 (m, 2H), 3.65 (d, 1H), 3.31-3.23 (m, 2H),3.02-2.91 (m, 1H), [M + H]⁺; 2.57-2.25 (m, 5H), 1.79-1.74 (m, 1H), 1.16(t, 3H). F9 ¹H NMR (600 MHz, DMSO-d₆): δ 12.88 (br, 1H), 10.07 (br, 1H),8.02 MS (ESI, pos.ion) (d, 1H), 7.93 (d, 1H), 7.56 (dd, 1H), 7.39 (dd,1H), 7.23 (td, 1H), 6.01 m/z: 539.1 (s, 1H), 4.25 (d, 1H), 4.04 (d, 1H),3.99 (dd, 1H), 3.84 (dd, 1H), 3.73-3.70 [M + H]⁺; (m, 1H), 3.69-3.65 (m,1H), 3.62-3.58 (m, 1H), 3.51 (s, 3H), 3.10-3.07 (m, 1H), 2.41-2.39 (m,1H). F10 ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 9.69 (s, 1H), 8.01(d, 1H), MS (ESI, pos.ion) 7.93 (d, 1H), 7.56 (dd, 1H), 7.38 (dd, 1H),7.23 (td, 1H), 6.01 (s, 1H), m/z: 567.2 3.93-3.83 (m, 3H), 3.60-3.53 (m,2H), 3.52 (s, 3H), 2.77 (dd, 2H), 2.38-2.25 [M + H]⁺; (m, 3H), 2.05-1.99(m, 1H), 1.65-1.59 (m, 2H). F11 ¹H NMR (600 MHz, DMSO-d₆): δ 12.06 (s,1H), 9.70 (s, 1H), 8.03 (d, 1H), MS (ESI, pos.ion) 7.94 (d, 1H), 7.57(dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.02 (s, 1H), 3.95 m/z: 567.2(d, 1H), 3.86-3.80 (m, 2H), 3.56-3.54 (m, 1H), 3.53 (s, 3H), 3.52-3.49[M + H]⁺; (m, 1H), 2.88 (d, 1H), 2.62 (d, 1H), 2.37-2.21 (m, 3H),2.15-2.08 (m, 1H), 1.72-1.64 (m, 2H). F12 ¹H NMR (400 MHz, DMSO-d6): δ9.87 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), MS (ESI, pos.ion) 7.56 (dd,1H), 7.38 (dd, 1H), 7.23 (td, 1H), 6.01 (s, 1H), 4.18 (d, 1H), 3.91 m/z:567.2 (d, 1H), 3.83-3.79 (m, 1H), 3.75-3.70 (m, 1H), 3.61-3.56 (m, 1H),3.53 [M + H]⁺; (s, 3H), 3.47-3.40 (m, 1H), 3.04-2.86 (m, 1H), 2.77-2.75(m, 1H), 2.58-2.54 (m, 1H), 2.37-2.22 (m, 2H), 1.88-1.84 (m, 1H),1.65-1.58 (m, 1H). F13 ¹H NMR (400 MHz, DMSO-d₆): δ 13.02 (s, 1H), 9.83(s, 1H), 8.02 (d, 1H), MS (ESI, pos.ion) 7.94 (d, 1H), 7.56 (dd, 1H),7.38 (dd, 1H), 7.22 (td, 1H), 5.99 (s, 1H), 4.05 m/z: 553.0 (d, 1H),3.90-3.85 (m, 1H), 3.75-3.60 (m, 3H), 3.52 (s, 3H), 3.47-3.42 [M + H]⁺;(m, 1H), 3.00 (d, 1H), 2.92 (d, 1H), 1.21 (d, 3H). F14 ¹H NMR (400 MHz,DMSO-d₆): δ 12.10 (s, 1H), 9.75 (s, 1H), 8.01 (d, 1H), MS (ESI, pos.ion)7.96 (d, 1H), 7.54 (dd, 1H), 7.40 (dd, 1H), 7.20 (td, 1H), 6.02 (s, 1H),4.18 m/z: 581.2 (d, 1H), 3.88 (d, 1H), 3.78-3.73 (m, 1H), 3.60-3.54 (m,1H), 3.52 (s, 3H), [M + H]⁺; 3.50-3.45 (m, 1H), 2.68 (d, 1H), 2.47-2.41(m, 1H), 2.36-2.30 (m, 3H), 2.04-1.92 (m, 1H), 1.81-1.73 (m, 1H), 1.21(d, 3H). F15 ¹H NMR (600 MHz, DMSO-d₆): δ 9.71 (br, 1H), 7.98 (d, 1H),7.91 (d, 1H), MS (ESI, pos.ion) 7.56 (dd, 1H), 7.40 (dd, 1H), 7.23 (td,1H), 5.99 (s, 1H), 4.33 (d, 1H), 4.09 m/z: 558.6 (d, 1H), 3.93-3.88 (m,1H), 3.52 (s, 3H), 3.49-3.45 (m, 1H), 3.22-3.08 [M + H]⁺; (m, 2H),2.82-2.74 (m, 1H). F16 ¹H NMR (400 MHz, DMSO-d₆): δ 11.03 (s, 1H), 9.57(s, 1H), 7.99 (d, 1H), MS (ESI, pos.ion) 7.92 (d, 1H), 7.55 (dd, 1H),7.39 (dd, 1H), 7.23 (td, 1H), 6.00 (s, 1H), 4.14 m/z: 587.2 (dd, 2H),3.62-3.54 (m, 1H),3.53 (s, 3H), 3.05-2.96 (m, 2H), 2.57-2.56 [M + H]⁺;(m, 1H), 2.36-2.20 (m, 2H), 2.13-1.98 (m, 1H), 1.95-1.90 (m, 1H),1.56-1.46 (m, 1H). F17 ¹H NMR (400 MHz, CDCl₃): δ 12.15 (br, 1H), 9.47(s, 1H), 7.85 (d, 1H), MS (ESI, pos.ion) 7.51 (d, 1H), 7.38-7.33 (m,2H), 7.01 (td, 1H), 6.17 (s, 1H), 4.50 (d, 1H), m/z: 587.2 3.66 (d, 1H),3.55 (s, 3H), 3.33-3.23 (m, 2H), 3.04-2.92 (m, 1H), 2.58-2.25 [M + H]⁺;(m, 5H), 1.78-1.74 (m, 1H).

Example 6: The Preparation of (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (500 g) and lithium (2.43 g,0.35 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(49.6 g, 0.1 mol) was added. The reaction mixture was stirred at 78° C.for 6 hours. After the reaction, the reaction mixture was cooled to 10°C., kept at 10° C. and stirred for 8 hours. The mixture was filtered.The filter cake was washed with anhydrous ethanol (50 g) and water (500g) in turn, and then dried in vacuo at 60° C. for 8 hours to obtain theproduct as a yellowish solid (31.8 g, 75%).

[a]_(D) ²⁵=80.71 (c=0.3023 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 424.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.88 (s, 1H), 7.97 (d, 1H), 7.89 (d, 1H),7.54 (dd, 1H), 7.35 (dd, 1H), 7.23 (td, 1H), 5.96 (s, 1H), 3.93 (q, 2H),2.46 (s, 3H), 1.03 (t, 3H).

The compound G can be prepared under the reaction conditions shown intable 9 according to the procedure described in step 1 of Example 6.

TABLE 9 The reaction conditions for preparation of compound G

The mole ratio The mass of Lithium to ratio of compound (5); reactionthe amount of solvent to Reaction Quality; compound (5) Reactioncompound temperature Reaction Product yield (%) of No. R³ is 49.6 gsolvent (5) (° C.) time(h) character product G1 ethyl 2.5 ethanol 10 7812 yellow solid 19.5 g; 46 G1 ethyl 3 ethanol 6 78 8 yellow solid 31.8g; 75 G1 ethyl 4 ethanol 10 78 4 yellow solid 29.7 g; 70 G1 ethyl 5ethanol 20 78 24 yellow solid 24.2 g; 57 G1 ethyl 6 ethanol 30 78 12yellow solid 20.4 g; 48 G1 ethyl 8 ethanol 20 78 12 yellow solid 25.4 g;60 G2 methyl 3 methanol 3 64 20 yellow solid 25.4 g; 62 G2 methyl 3methanol 4 64 6 yellow solid 18.5 g; 45 G2 methyl 4 methanol 6 64 8yellow solid 15.6 g; 38

TABLE 9-1 The NMR, MS and specific rotation datum of the compound G No.¹H NMR MS specific rotation G1 ¹H NMR (400 MHz, DMSO-d₆): δ 9.88 (s,1H), 7.97 MS (ESI, pos.ion) [a]_(D) ²⁵ = −80.71 (d, 1H), 7.89 (d, 1H),7.54 (dd, 1H), 7.35 (dd, 1H), 7.23 m/z: 424.0 (c = 0.3023 g/100 (td,1H), 5.96 (s, 1H), 3.93 (q, 2H), 2.46 (s, 3H), 1.03 [M + H]⁺; mL, MeOH);(t, 3H). G2 ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (d, 1H), 7.67 MS (ESI,pos.ion) [a]_(D) ²⁵ = −86.04 (d, 1H), 7.42 (dd, 2H), 7.36 (dd, 1H), 7.15(td, 1H), 5.85 m/z: 410.0 (c = 0.3022 g/100 (s, 1H), 3.40 (s, 3H), 2.33(s, 3H). [M + H]⁺; mL, MeOH);

Step 2) (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(42.4 g, 0.1 mol) and CCl₄ (800 mL), followed by NBS (19.6 g, 0.11 mol)at 70° C. The mixture was stirred for 30 min. After the reaction, themixture was cooled and filtered. The filtrate was concentrated to obtainthe product as a yellow solid (34.2 g, 68%).

MS (ESI, pos.ion) m/z: 503.9 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 10.23 (s, 1H), 8.01 (d, 1H), 7.98 (d, 1H),7.62 (dd, 1H), 7.42 (dd, 1H), 7.29 (td, 1H), 6.01 (s, 1H), 4.79 (br,2H), 4.01 (q, 2H), 1.08 (t, 3H).

The compound J can be prepared under the reaction conditions shown intable 10 according to the procedure described in step 2 of Example 6.

TABLE 10 The reaction conditions for preparation of compound J

The mass The mole ratio of ratio of NBS to compound reaction ReactionQuality; G; the amount of Reaction solvent to temperature Product yield(%) No. R³ compound G solvent compound G (° C.) character of product J1ethyl 1.0; 42.4 g DCM 10 39 yellow solid 35.2 g; 70 J1 ethyl 1.0; 42.4 gCHCl₃ 20 61 yellow solid 36.3 g; 72 J1 ethyl 1.1; 42.4 g CCl₄ 30 76yellow solid 44.3 g; 88 J2 methyl 1.0; 41 g   DCM 10 39 yellow solid29.9 g; 73 J2 methyl 1.1; 41 g   CHCl₃ 20 61 yellow solid 30.8 g; 75 J2methyl 1.1; 41 g   CCl₄ 30 76 yellow solid 34.9 g; 85

TABLE 10-1 The NMR and MS datum of compound J No. ¹H NMR MS J1 ¹H NMR(600 MHz, DMSO-d₆): δ 10.23 (s, 1H), 8.01 (d, 1H), 7.98 (d, 1H), MS(ESI, pos.ion) 7.62 (dd, 1H), 7.42 (dd, 1H), 7.29 (td, 1H), 6.01 (s,1H), 4.79 (br, 2H), m/z: 503.9 4.01 (q, 2H), 1.08 (t, 3H). [M + H]⁺; J2¹H NMR (400 MHz, CDCl₃): δ 8.87 (d, 1H), 7.54 (d, 1H), 7.4(dd, 1H), MS(ESI, pos.ion) 7.35 (dd, 1H), 7.03 (td, 1H), 6.11 (s, 1H), 4.97 (d, 1H),4.64 (d, 1H), m/z: 489.9 3.69 (s, 3H). [M + H]⁺;

Step 3) (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(50.3 g, 0.1 mol), anhydrous ethanol (302 g) and morpholine (34.8 g, 0.4mol). The mixture was stirred at 25° C. under nitrogen atmosphere for 6hours. After the reaction, the mixture was concentrated. To the residuewas added ethyl acetate (500 g), the resulting mixture was washed withwater (250 mL×2). The organic layer was concentrated to give the productas tawny oil (37.7 g, 74%)

MS (ESI, pos.ion) m/z: 509.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H),7.57 (dd, 1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.05 (s, 1H), 3.96 (q, 4H),3.93 (dd, 2H), 3.68 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).

The compound L can be prepared under the reaction conditions shown intable 11 according to the procedure described in step 3 of Example 6.

TABLE 11 The reaction conditions for preparation of compound L

The mole ratio of compound The mass (6) to compound ratio of (J);reaction Reaction Quality; the amount of Reaction solvent to temperatureReaction Product yield (%) of No. R³ compound J solvent compound (J) (°C.) time(h) character product L1 ethyl 2; 50.3 g ethanol 20 25 2 tawnyoil 38.2 g; 75 L1 ethyl 3; 50.3 g acetone 10 40 10 tawny oil 40.8 g; 80L1 ethyl 4; 50.3 g methanol 10 30 6 tawny oil 38.7 g; 76 L1 ethyl 5;50.3 g ethyl 20 50 24 tawny oil 35.7 g; 70 acetate L1 ethyl 6; 50.3 gDCM 8 39 6 tawny oil 36.2 g; 71 L1 ethyl 3; 50.3 g DMF 4 60 1 tawny oil36.7 g; 72 L1 ethyl 4; 50.3 g THF 6 50 8 tawny oil 38.2 g; 75 L2 methyl2; 48.9 g ethanol 20 25 2 tawny oil 36.2 g; 73 L2 methyl 3; 48.9 gacetone 10 40 10 tawny oil 37.6 g; 76 L2 methyl 4; 48.9 g methanol 10 306 tawny oil 39.6 g; 80 L2 methyl 5; 48.9 g ethyl 20 50 24 tawny oil 38.6g; 78 acetate L2 methyl 6; 48.9 g DCM 8 39 6 tawny oil 35.2 g; 71 L2methyl 3; 48.9 g DMF 4 60 1 tawny oil 36.2 g; 73 L2 methyl 4; 48.9 g THF6 50 8 tawny oil 35.7 g; 72

TABLE 11-1 The NMR and MS datum of compound L No. ¹H NMR MS L1 ¹H NMR(600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.02 (d, 1H), 7.93 (d, 1H), MS (ESI,pos. ion) 7.57 (dd, 1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.05 (s, 1H),3.96 (q, 4H), 3.93 m/z: 509.1 (dd, 2H), 3.68 (br, 4H), 2.56 (br, 4H),1.05 (t, 3H). [M + H]⁺; L2 ¹H NMR (600 MHz, DMSO-d₆): δ 9.71 (s, 1H),8.02 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) 7.55 (dd, 1H), 7.37 (dd,1H), 7.20 (td, 1H), 6.02 (s, 1H), 3.91 (dd, 2H), 3.67 m/z: 494.7 (br,4H), 3.52 (s, 3H), 2.55 (br, 4H). [M + H]⁺;

Example 7: The Preparation of(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added (R)-ethyl4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(5.03 g, 10 mmol), (S)-morpholine-3-carboxylic acid (1.31 g, 10 mmol),potassium carbonate (2.76 g, 20 mmol) and ethanol (100 mL). The mixturewas stirred at 30° C. under nitrogen atmosphere for 12 hours. After thereaction, the mixture was filtered. The filtrate was concentrated. Tothe residue was added water (100 mL), the resulting mixture wasextracted with ethyl acetate (100 mL). The organic layer was discarded.To the aqueous layer was added ethyl acetate (100 mL), the mixture wasadjusted to pH 3-6 with concentrated hydrochloric acid. The organiclayer was dried over anhydrous sodium sulfate and concentrated to givethe product as a yellow solid (4.4 g, 80%).

MS (ESI, pos.ion) m/z: 553.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 12.85 (br, 1H), 9.80 (s, 1H), 8.00 (d, 1H),7.91 (d, 1H), 7.54 (dd, 1H), 7.39 (dd, 1H), 7.19 (td, 1H), 6.01 (s, 1H),4.25 (d, 1H), 4.02 (d, 1H), 3.97-3.91 (m, 3H), 3.81 (dd, 1H), 3.72-3.69(m, 1H), 3.66-3.63 (m, 1H), 3.61-3.58 (m, 1H), 3.10-3.03 (m, 1H),2.42-2.35 (m, 1H), 1.04 (t, 3H).

The compound F can be prepared under the reaction conditions shown intable 12 according to the procedure described in Example 7.

TABLE 12 The reaction conditions for preparation of compound F

No. R³

The mole ratio of compound (J) to compound (VI); the amount of compound(J) Reaction solvent The mass ratio of reaction solvent to compound (J)Reaction temperature (° C.) Reaction time(h) Product character Quality;yield (%) of product F1 ethyl

1; 5.03 g ethanol 8 30 4 yellow solid 4.07 g; 70 F2 ethyl

1; 5.03 g ethanol 4 30 8 yellow solid 4.12 g; 71 F3 ethyl

1; 5.03 g ethanol 20 30 24 yellow solid 2.61 g; 45 F4 ethyl

1; 5.03 g ethanol 30 30 6 yellow solid 4.54 g; 80 F5 ethyl

1; 5.03 g ethanol 15 30 24 yellow solid 3.04 g; 51 F6 ethyl

1; 5.03 g ethanol 20 30 6 yellow solid 4.47 g; 78 F7 ethyl

1; 5.03 g ethanol 25 30 12 yellow solid 3.91 g; 65 F8 ethyl

1; 5.03 g ethanol 14 30 12 yellow solid 4.09 g; 68 F9 methyl

1; 4.89 g ethanol 8 30 4 yellow solid 3.83 g; 71 F10 methyl

1; 4.89 g ethanol 4 30 8 yellow solid 3.85 g; 68 F11 methyl

1; 4.89 g ethanol 10 30 12 yellow solid 3.74 g; 66 F12 methyl

1; 4.89 g ethanol 30 30 6 yellow solid 2.50 g; 44 F13 methyl

1; 4.89 g ethanol 8 30 12 yellow solid 4.32 g; 78 F14 methyl

1; 4.89 g ethanol 20 30 6 yellow solid 2.79 g; 48 F15 methyl

1; 4.89 g ethanol 25 30 12 yellow solid 4.14 g; 74 F16 methyl

1; 4.89 g ethanol 14 30 12 yellow solid 3.64 g; 62 F17 methyl

1; 4.89 g ethanol 15 30 24 yellow solid  3.7 g; 63

TABLE 12-1 The NMR and MS datum of compound L No. ¹H NMR MS F1 ¹H NMR(400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.65 (s, 1H), 8.02 (d, 1H), MS(ESI, pos. ion) 7.94 (d, 1H), 7.57 (dd, 1H), 7.39 (dd, 1H), 7.22 (td,1H), 6.03 (s, 1H), 3.96 m/z: 581.2 (q, 2H), 3.89-3.85 (m, 3H), 3.61-3.47(m, 2H), 2.81-2.75 (m, 2H), 2.38-2.21 [M + H]⁺; (m, 3H), 2.04-2.02 (m,1H), 1.65-1.60 (m, 2H), 1.06 (t, 3H). F2 ¹H NMR (400 MHz, DMSO-d₆): δ12.06 (s, 1H), 9.66 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.95 (d,1H), 7.56 (dd, 1H), 7.41 (dd, 1H), 7.20 (td, 1H), 6.03 (s, 1H), 3.97m/z: 580.9 (q, 2H), 3.93-3.83 (m, 3H), 3.57-3.46 (m, 2H), 2.88 (d, 1H),2.63 (d, 1H), [M + H]⁺; 2.37-2.22 (m, 3H), 2.13-2.08 (m, 1H), 1.75-1.65(m, 2H), 1.06 (t, 3H). F3 ¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (br, 1H),9.82 (s, 1H), 8.02 MS (ESI, pos. ion) (d, 1H), 7.92 (d, 1H), 7.54( dd,1H), 7.40 (dd, 1H), 7.22 (td, 1H), 6.03 (s, 1H), m/z: 580.9 4.18 (d,1H), 3.96 (q, 2H), 3.91 (d, 1H), 3.82-3.79 (m, 1H), 3.74-3.71 [M + H]⁺;(m, 1H), 3.61-3.57 (m, 1H), 3.37-3.32 (m, 1H), 2.78-2.75 (m, 1H),2.57-2.53 (m, 1H), 2.49-2.47 (m, 1H), 2.38-2.32 (m, 2H), 1.89-1.84 (m,1H), 1.68-1.58 (m, 1H), 1.06 (t, 3H). F4 ¹H NMR (400 MHz, DMSO-d₆): δ13.02 (s, 1H), 9.78 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.93 (d,1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.22 (td, 1H), 6.00 (s, 1H), 4.10m/z: 567.1 (d, 1H), 3.95 (q, 2H), 3.90-3.87 (m, 1H), 3.76-3.60 (m, 3H),3.46-3.42 [M + H]⁺; (m, 1H), 2.98 (d, 1H), 2.93 (d, 1H), 1.21 (d, 3H),1.05 (t, 3H). F5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.74 (s,1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.56 (dd, 1H), 7.39(dd, 1H), 7.19 (td, 1H), 6.04 (s, 1H), 4.16 m/z: 594.6 (d, 1H),4.00-3.93 (m, 2H), 3.86 (d, 1H), 3.77-3.72 (m, 1H), 3.59-3.53 [M + H]⁺;(m, 1H), 3.51-3.45 (m, 1H), 2.66 (d, 1H), 2.46-2.40 (m, 1H), 2.37-2.30(m, 3H), 2.03 -1.91 (m, 1H), 1.80-1.73 (m, 1H), 1.20 (d, 3H), 1.06 (t,3H). F6 ¹H NMR (600 MHz, DMSO-d₆): δ 9.98 (br, 1H), 8.03 (d, 1H), 8.00(d, 1H), MS (ESI, pos. ion) 7.61 (dd, 1H), 7.48 (dd, 1H), 7.28 (td, 1H),6.02 (s, 1H), 4.35 (d, 1H), 4.13 m/z: 573.0 (d, 1H), 4.01-3.94 (m, 3H),3.61-3.51 (m, 1H), 3.25-3.19 (m, 1H), 3.10-3.04 [M + H]⁺; (m, 1H),2.86-2.68 (m, 1H), 1.20 (t, 3H). F7 ¹H NMR (600 MHz, DMSO-d₆): δ 12.08(s, 1H), 9.51 (s, 1H), 8.01 (d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H),7.57 (dd, 1H), 7.41 (dd, 1H), 7.24 (td, 1H), 6.01 (s, 1H), 4.12 m/z:601.1 (dd, 2H), 3.97 (q, 2H), 3.61-3.52 (m, 1H), 3.04-2.96 (m, 2H),2.58-2.56 [M + H]⁺; (m, 1H), 2.35-2.20 (m, 2H), 2.12-1.98 (m, 1H),1.93-1.90 (m, 1H), 1.56-1.48 (m, 1H), 1.06 (t, 3H). F8 ¹H NMR (400 MHz,CDCl₃): δ 12.19 (br, 1H), 9.46 (s, 1H), 7.86 (d, 1H), MS (ESI, pos. ion)7.50 (d, 1H), 7.37-7.33 (m, 2H), 7.00 (td, 1H), 6.19 (s, 1H), 4.52 (d,1H), m/z: 601.2 4.14-4.03(m, 2H), 3.65(d, 1H), 3.31-3.23 (m, 2H),3.02-2.91 (m, 1H), [M + H]⁺; 2.57-2.25 (m, 5H), 1.79-1.74 (m, 1H), 1.16(t, 3H). F9 ¹H NMR (600 MHz, DMSO-d₆): δ 12.88 (br, 1H), 10.07 (br, 1H),8.02 MS (ESI, pos. ion) (d, 1H), 7.93 (d, 1H), 7.56 (dd, 1H), 7.39 (dd,1H), 7.23 (td, 1H), 6.01 (s, 1H), m/z: 539.1 4.25 (d, 1H), 4.04 (d, 1H),3.99 (dd, 1H), 3.84 (dd, 1H), 3.73-3.70 (m, 1H), [M + H]⁺; 3.69-3.65 (m,1H), 3.62-3.58 (m, 1H), 3.51 (s, 3H), 3.10-3.07 (m, 1H), 2.41-2.39 (m,1H). F10 ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 9.69 (s, 1H), 8.01(d, 1H), MS (ESI, pos. ion) 7.93 (d, 1H), 7.56 (dd, 1H), 7.38 (dd, 1H),7.23 (td, 1H), 6.01 (s, 1H), m/z: 567.2 3.93-3.83 (m, 3H), 3.60-3.53 (m,2H) 3.52 (s, 3H), 2.77 (dd, 2H), 2.38-2.25 [M + H]⁺; (m, 3H), 2.05-1.99(m, 1H), 1.65-1.59 (m, 2H). F11 ¹H NMR (600 MHz, DMSO-d₆): δ 12.06 (s,1H), 9.70 (s, 1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.57(dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.02 (s, 1H), 3.95 m/z: 567.2(d, 1H), 3.86-3.80 (m, 2H), 3.56-3.54 (m, 1H), 3.53 (s, 3H), 3.52-3.49[M + H]⁺; (m, 1H), 2.88 (d, 1H), 2.62 (d, 1H), 2.37-2.21 (m, 3H),2.15-2.08 (m, 1H), 1.72-1.64 (m, 2H). F12 ¹H NMR (400 MHz, DMSO-d₆): δ9.87 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), MS (ESI, pos. ion) 7.56 (dd,1H), 7.38 (dd, 1H), 7.23 (td, 1H), 6.01 (s, 1H), 4.18 (d, 1H), 3.91 m/z:567.2 (d, 1H), 3.83-3.79 (m, 1H), 3.75-3.70 (m, 1H), 3.61-3.56 (m, 1H),3.53 [M + H]⁺; (s, 3H), 3.47-3.40 (m, 1H), 3.04-2.86 (m, 1H), 2.77-2.75(m, 1H), 2.58-2.54 (m, 1H), 2.37-2.22 (m, 2H), 1.88-1.84 (m, 1H),1.65-1.58 (m, 1H). F13 ¹H NMR (400 MHz, DMSO-d₆): δ 13.02 (s, 1H), 9.83(s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.56 (dd, 1H),7.38 (dd, 1H), 7.22 (td, 1H), 5.99 (s, 1H), 4.05 m/z: 553.0 (d, 1H),3.90-3.85 (m, 1H), 3.75-3.60 (m, 3H), 3.52 (s, 3H), 3.47-3.42 [M + H]⁺;(m, 1H), 3.00 (d, 1H), 2.92 (d, 1H), 1.21 (d, 3H). F14 ¹H NMR (400 MHz,DMSO-d₆): δ 12.10 (s, 1H), 9.75 (s, 1H), 8.01 (d, 1H), MS (ESI, pos.ion) 7.96 (d, 1H), 7.54 (dd, 1H), 7.40 (dd, 1H), 7.20 (td, 1H), 6.02 (s,1H), 4.18 m/z: 581.2 (d, 1H), 3.88 (d, 1H), 3.78-3.73 (m, 1H), 3.60-3.54(m, 1H), 3.52 (s, 3H), [M + H]⁺; 3.50-3.45 (m, 1H), 2.68 (d, 1H),2.47-2.41 (m, 1H), 2.36-2.30 (m, 3H), 2.04- 1.92 (m, 1H), 1.81-1.73 (m,1H), 1.21 (d, 3H). F15 ¹H NMR (600 MHz, DMSO-d₆): δ 9.71 (br, 1H), 7.98(d, 1H), 7.91 (d, 1H), MS (ESI, pos. ion) 7.56 (dd, 1H), 7.40 (dd, 1H),7.23 (td, 1H), 5.99 (s, 1H), 4.33 (d, 1H), 4.09 m/z: 558.6 (d, 1H),3.93-3.88 (m, 1H), 3.52 (s, 3H), 3.49-3.45 (m, 1H), 3.22-3.08 [M + H]⁺;(m, 2H), 2.82-2.74 (m, 1H). F16 ¹H NMR (400 MHz, DMSO-d₆): δ 11.03 (s,1H), 9.57 (s, 1H), 7.99 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.55(dd, 1H), 7.39 (dd, 1H), 7.23 (td, 1H), 6.00 (s, 1H), 4.14 m/z: 587.2(dd, 2H), 3.62-3.54 (m, 1H), 3.53 (s, 3H), 3.05-2.96 (m, 2H), 2.57-2.56[M + H]⁺; (m, 1H), 2.36-2.20 (m, 2H), 2.13-1.98 (m, 1H), 1.95-1.90 (m,1H), 1.56-1.46 (m, 1H). F17 ¹H NMR (400 MHz, CDCl₃): δ 12.15 (br, 1H),9.47 (s, 1H), 7.85 (d, 1H), MS (ESI, pos. ion) 7.51 (d, 1H), 7.38-7.33(m, 2H), 7.01 (td, 1H), 6.17 (s, 1H), 4.50 (d, 1H), m/z: 587.2 3.66 (d,1H) 3.55 (s, 3H), 3.33-3.23 (m, 2H), 3.04-2.92 (m, 1H), 2.58-2.25 [M +H]⁺; (m, 5H), 1.78-1.74 (m, 1H).

Example 8: The Preparation of (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Method One:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2-chloro-4-fluorobenzaldehyde (15.9 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (74 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, themixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours.The resulting mixture was filtered. The filter cake was washed withwater (330 mL) and dried in vacuo at 60° C. for 8 hours to obtain thecrude product. To the crude product was added n-propanol (50 g). Themixture was heated until dissolved completely, cooled to 30° C., andthen kept at 30° C., stirred and crystallized for 8 hours. The resultingmixture was filtered. The filter cake was dried in vacuo at 60° C. for 8hours to obtain the product as a yellow solid (10.4 g, 23%).

[a]_(D) ²⁵=−91.47 (c=0.3083 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 452.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.05 (s, 1H), 7.98 (d, 1H), 7.91 (d, 1H),7.42-7.37 (m, 2H), 7.20 (td, 1H), 6.03 (s, 1H), 4.84 (q, 1H), 4.12-4.04(m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.14 (t, 3H).

The compound 8 can be prepared under the reaction conditions shown intable 13 by using method one described in step 1 of Example 8.

TABLE 13 The reaction conditions

The (1):(7): mass (3):(4): ratio (mol); of The mass the reaction ratioof amount solvent recrystalli- of to Reaction Re- Cool- zationCrystalliza- Quality; compound com- tempera- action Cooling ingRecrystalli- solvent to tion Crystalli- yield (%) (1) is Reaction poundture time temperature time zation compound temperature zation of No.16.4 g sovent (1) (° C.) (h) (° C.) (h) solvent (1) (° C.) time(h)product 1 1:1:2:1 — — 78 12 40 6 ethanol 20 0 3 7.9 g; 17.5 2 1:1:1:1ethanol 1 78 12 40 6 ethanol 15 25 10 8.5 g; 18.8 3 1:1:1:1 ethanol 4.525 72 25 — ethanol 4 5 8 9.1 g; 20.2 4 1:1:1:1 ethanol 5 78 12 25 6ethanol 3 15 5 10.2 g;  22.5 5 1:1:1:1 ethanol 20 60 24 −20 12 ethanol 325 6 8.9 g; 19.6 6 1:1:1:1 ethanol 80 78 12 −40 24 ethanol 5 25 4 7.6 g;16.9 7 1:1:1:1 n-butanol 4.5 100 5 25 6 n-butanol 4 25 6 10.4 g;  23.1 81:1:1:1 n-propanol 4.5 80 12 25 6 n-propanol 3 25 6 11.8 g;  26.2 91:1:1:1 i-propanol 4.5 82 12 25 2 i-propanol 3 30 6 11.4 g;  25.3 101:1:1:1 t-butanol 4.5 82 12 30 12 t-butanol 4 25 6  11 g; 24.4 111:1:1:1 2-methoxy- 4.5 78 12 −10 12 i-propanol 3.5 25 4 9 g; ethanol20   12 1:1:1:1 1,2-di- 4.5 78 12 −15 12 i-propanol 3.5 25 6 8.6 g;methoxy- 19.1 ethaneMethod Two

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2-chloro-4-fluorobenzaldehyde (15.9 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (74 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, thereaction mixture was cooled to 30° C., kept at 30° C. and stirred for 6hours. The mixture was filtered. The filtrate was washed with ethanol(16.4 g) and water (330 mL) in turn, and then dried in vacuo at 60° C.for 8 hours to obtain the product as a yellow solid (12.2 g, 27%).

[a]_(D) ²⁵=−91.47 (c=0.3083 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 452.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.05 (s, 1H), 7.98 (d, 1H), 7.91 (d, 1H),7.42-7.37 (m, 2H), 7.20 (td, 1H), 6.03 (s, 1H), 4.84 (q, 1H), 4.12-4.04(m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.14 (t, 3H).

The compound 8 can be prepared under the reaction conditions shown intable 14 by using method two described in step 1 of Example 8.

TABLE 14 The reaction conditions

(1):(7): (3):(4): The The (mol); mass mass the ratio of ratio of amountreaction washing of solvent solvent compound to Reaction Cooling toWashing Quality; (1) is Reaction compound tempera- Reaction tempera-Cooling Washing compound temperature yield (%) No. 16.4 g sovent (1)ture time(h) ture(° C.) time(h) solvent (1) (° C.) of product 1 1:1:2:1— — 78 12 40 6 ethanol 10 25  8.8 g; 19.4 2 1:1:1:1 ethanol 1 78 12 40 6ethanol 7.5 25  9.3 g; 20.5 3 1:1:1:1 ethanol 4.5 25 72 25 — ethanol 225   10 g; 22.2 4 1:1:1:1 ethanol 5 78 12 25 6 ethanol 3 25 11.1 g; 24.65 1:1:1:1 n-propanol 6 80 12 25 6 — — — 13.1 g; 28.9 6 1:1:1:1 ethanol20 60 24 −20 6 ethanol 3 25  9.6 g; 21.3 7 1:1:1:1 ethanol 80 78 12 −3024 ethanol 5 25  9.3 g; 18.8 8 1:1:1:1 n-butanol 4.5 100 5 25 6n-butanol 3 25 11.4 g; 25.2 9 1:1:1:1 n-propanol 4.5 80 12 25 6n-propanol 2 25 12.8 g; 28.4 10 1:1:1:1 i-propanol 4.5 82 12 25 2i-propanol 2 30 12.6 g; 27.8 11 1:1:1:1 t-butanol 4.5 82 12 30 12t-butanol 3 25   12 g; 26.5 12 1:1:1:1 2-methoxy- 4.5 78 12 −10 122-methoxy- 1 0  9.9 g; ethanol ethanol 21.8 13 1:1:1:1 1,2-di- 4.5 78 12−15 12 i-propanol 2 25  9.6 g; methoxy- 21.3 ethaneMethod Three:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2-chloro-4-fluorobenzaldehyde (15.9 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (74 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, themixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours.The resulting mixture was filtered. The filter cake was washed withwater (330 mL) and dried in vacuo at 60° C. for 8 hours to obtain thecrude product. The crude product was triturated with n-propanol (50 g)at 30° C. for 5 hours and filtered. The filter cake was dried in vacuoat 60° C. for 8 hours to obtain the product as a yellow solid (11.3 g,25%).

[a]_(D) ²⁵=−91.47 (c=0.3083 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 452.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.05 (s, 1H), 7.98 (d, 1H), 7.91 (d, 1H),7.42-7.37 (m, 2H), 7.20 (td, 1H), 6.03 (s, 1H), 4.84 (q, 1H), 4.12-4.04(m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.14 (t, 3H).

The compound 8 can be prepared under the reaction conditions shown intable 15 by using method three described in step 1 of Example 8.

TABLE 15 The reaction conditions

(1):(7): (3):(4): The (mol); mass the ratio of The mass amount reactionCool- ratio of of solvent Reaction ing trituration Trituration Quality;compound to temper- temper- solvent to tempera- yield (%) (1) isReaction compound ature Reaction ature Cooling Trituration compound tureTrituration of No. 16.4 g sovent (1) (° C.) time(h) (° C.) time(h)solvent (1) (° C.) time(h) product 1 1:1:2:1 — — 78 12 40 6 ethanol 8 2510 8.4 g; 18.6 2 1:1:1:1 ethanol 1 78 12 40 6 ethanol 7 25 5 8.8 g; 19.53 1:1:1:1 ethanol 4.5 25 72 25 — ethanol 3 25 3 9.6 g; 21.3 4 1:1:1:1ethanol 5 78 12 25 6 ethanol 4 5 1 10.5 g;  23.2 5 1:1:1:1 ethanol 20 6024 −20 12 ethanol 3 25 4 9.3 g; 20.6 6 1:1:1:1 ethanol 80 78 12 -40 24ethanol 5 25 2 8.1 g; 17.8 7 1:1:1:1 n-butanol 4.5 100 5 25 6 n-butanol4 25 3 10.9 g;  24.1 8 1:1:1:1 n-propanol 4.5 80 12 25 6 n-propanol 3 254 12.4 g;  27.5 9 1:1:1:1 i-propanol 4.5 82 12 25 2 i-propanol 3 30 212.1 g;  26.7 10 1:1:1:1 t-butanol 4.5 82 12 30 12 t-butanol 4 25 4 11.4g;  25.3 11 1:1:1:1 2-methoxy- 4.5 78 12 −10 12 i-propanol 3 25 3 9.4 g;ethanol 20.9 12 1:1:1:1 1,2-di- 4.5 78 12 −15 12 i-propanol 3 25 2 9.2g; methoxy- 20.4 ethane

Step 2) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-bromomethyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(45.2 g, 0.1 mol) and tetrachloromethane (900 g). The mixture was heatedat 76° C., NBS was added (19.6 g, 0.11 mol), and then the reactionmixture was stirred for 30 min. After the reaction, the reaction mixturewas cooled and concentrated. To the residue was added ethanol (226 g).The resulting mixture was cooled to 0° C., kept at 0° C. and stirred.After the solid precipitated out completely, the mixture was filtered.The filter cake was washed with ethanol (45 g) and dried in vacuo at 60°C. for 6 hours to obtain the product as a yellow solid (31.3 g, 59%).

MS (ESI, pos.ion) m/z: 531.6 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.37 (s, 1H), 8.03 (d, 1H), 8.00 (d, 1H),7.47-7.42 (m, 2H), 7.23 (td, 1H), 6.01 (s, 1H), 4.94 (q, 1H), 4.87-4.78(m, 2H), 4.16-4.04 (m, 2H), 1.27 (d, 3H), 1.15 (t, 3H).

The compound A2 can be prepared under the reaction conditions shown intable 16 according to the procedure described in step 2 of Example 8.

TABLE 16 The reaction conditions

The mass The mass Compound ratio of ratio of the (8):NBS(mol) reactionThe additional the amount of solvent to Reaction solvent solvent toQuality; compound (8) is Reaction compound temperature added to compoundyield (%) No. 45.2 g solvent (8) (° C.) the residue (8) of product 11:1.1, DCM 30 39 i-propanol 7 33.5 g; 63% 2  1:1.05, DCM 10 39 ethanol 531.9 g; 60% 3  1:1.15, CHCl₃ 20 61 n-propanol 6 34.5 g; 65% 4 1:1.1,CCl₄ 20 76 ethanol 5 36.1 g; 68%

Step 3) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-morpholinomethyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(53.1 g, 0.1 mol), i-propanol (287 g) and morpholine (34.8 g, 0.4 mol).The mixture was stirred at 55° C. for 4 hours. After the reaction, themixture was cooled to 0° C., kept at this temperature and stirred. Afterthe solid precipitated out completely, the mixture was filtered. Thefilter cake was washed with i-propanol (53 g) followed by water (530 g),and then dried in vacuo at 60° C. for 8 hours to obtain the product as ayellowish solid (34.4 g, 64%).

MS (ESI, pos.ion) m/z: 537.2 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.77 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H),7.44-7.41 (m, 2H), 7.18 (td, 1H), 6.09 (s, 1H), 4.86 (q, 1H), 4.12-4.04(m, 2H), 3.90 (dd, 2H), 3.68 (t, 4H), 2.56 (br, 4H), 1.25 (d, 3H), 1.14(t, 3H).

Step 4) (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (403 g) and lithium (1.74 g,0.25 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then a solution of(R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(53.7 g, 0.1 mol) in ethanol (403 g) was added. The reaction mixture wasstirred at 78° C. for 1.5 hours. After the reaction, the reactionmixture was cooled and concentrated. To the residue was added ethylacetate (540 g). The mixture was washed with water (250 g×2). Theorganic layer was concentrated to obtain the product as yellow thick oil(34.9 g, 75%).

MS (ESI, pos.ion) m/z: 465.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.00 (d, 1H), 7.91 (d, 1H),7.40-7.37 (m, 2H), 7.15 (td, 1H), 6.03 (s, 1H), 3.94 (q, 2H), 3.88 (dd,2H), 3.65 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).

Example 9: The Preparation of (R)-methyl4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous methanol (806 g) and lithium (1.74 g,0.25 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(53.7 g, 0.1 mol) was added. The reaction mixture was allowed to warm upto 60° C. and stirred for 1.5 hours. After the reaction, the reactionmixture was cooled and concentrated. To the residue was added ethylacetate (540 g). The mixture was washed with water (250 g×2). Theorganic layer was concentrated to obtain the product as yellow thick oil(32.9 g, 73%).

MS (ESI, pos.ion) m/z: 450.8 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.72 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H),7.43-7.38 (m, 2H), 7.17 (td, 1H), 6.05 (s, 1H), 3.93 (dd, 2H), 3.68 (br,4H), 3.53 (s, 3H), 2.56 (br, 4H).

Example 10: The Preparation of(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

Step 1)(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-((((R)-1-ethoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(53.1 g, 0.1 mol), ethanol (800 g), (S)-morpholine-3-carboxylic acid(13.1 g, 0.1 mol) and potassium carbonate (27.6 g, 0.2 mol) in turn. Themixture was stirred at 30° C. for 12 hours. After the reaction, themixture was filtered. The filtrate was concentrated. To the residue wasadded water (840 g), the resulting mixture was extracted with ethylacetate (840 mL), the organic layer was discarded. To the aqueous layerwas added ethyl acetate (900 mL), the mixture was adjusted to pH 3-6with concentrated hydrochloric acid. The organic layer was dried overanhydrous sodium sulfate and concentrated to give the product as ayellow solid (41.8 g, 72%).

MS (ESI, pos.ion) m/z: 581.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 8.01 (d, 1H), 7.96 (d, 1H), 7.43-7.39 (m,2H), 7.18 (td, 1H), 6.04 (s, 1H), 4.86 (q, 1H), 4.25-4.14 (m, 1H),4.11-4.02 (m, 3H), 3.99-3.87 (m, 1H), 3.84 (dd, 1H), 3.74-3.65 (m, 2H),3.57-3.51 (m, 1H), 3.11-3.04 (m, 1H), 2.43-2.38 (m, 1H), 1.22 (d, 3H),1.14 (t, 3H).

The compound Q can be prepared under the reaction conditions shown intable 17 according to the procedure described in step 1 of Example 10.

TABLE 17 The reaction conditions for preparation of compound Q

No.

compound A2: compound(VI)(mol); the amount of compound A1 is 5.31 gReaction solvent Reaction temperature (° C.) Reaction time(h) Productcharacter Quality; yield (%) of product Q1

1:1 ethanol 30 12 yellow solid 4.14 g; 68 Q2

1:1 ethanol 30 12 yellow solid 4.08 g; 67 Q3

1:1 ethanol 30 12 yellow solid 2.68 g; 44 Q4

1:1 ethanol 30 12 yellow solid 4.22 g; 71 Q5

1:1 ethanol 30 12 yellow solid 2.68 g; 43 Q6

1:1 ethanol 30 12 yellow solid 4.09 g; 68 Q7

1:1 ethanol 30 12 yellow solid  3.4 g; 54 Q8

1:1 ethanol 30 12 yellow solid  3.2 g; 51

TABLE 17-1 The NMR and MS datum of compound Q No. ¹H NMR MS Q1 ¹H NMR(600 MHz, DMSO-d₆): δ 12.03 (br, 1H), 9.76 (s, 1H), 8.02 MS (ESI, pos.ion) (d, 1H), 7.95 (d, 1H), 7.44-7.39 (m, 2H), 7.20 (td, 1H), 6.05 (s,1H), 4.86 m/z: 609.1 (q, 1H), 4.13-4.05 (m, 2H), 3.93-3.85 (m, 3H),3.59-3.56 (m, 1H), 3.53-3.48 [M + H]⁺; (m, 1H), 2.78 (t, 2H), 2.36-2.23(m, 3H), 2.01 (t, 1H), 1.65-1.62 (m, 2H), 1.24 (d, 3H), 1.13 (t, 3H). Q2¹H NMR (600 MHz, DMSO-d₆): δ 12.06 (br, 1H), 9.72 (s, 1H), 8.04 MS (ESI,pos. ion) (d, 1H), 7.96 (d, 1H), 7.43-7.39 (m, 2H), 7.19 (td, 1H), 6.04(s, 1H), 4.84 m/z: 608.7 (q, 1H), 4.14-4.06 (m, 2H), 3.94-3.86 (m, 3H),3.58-3.55 (m, 1H), 3.52-3.48 [M + H]⁺; (m, 1H), 2.77 (t, 2H), 2.37-2.23(m, 3H), 2.02 (t, 1H), 1.66-1.62 (m, 2H), 1.24 (d, 3H), 1.14 (t, 3H). Q3¹H NMR (600 MHz, DMSO-d₆): δ 9.78 (s, 1H), 8.04 (d, 1H), 7.96 (d, 1H),MS (ESI, pos. ion) 7.44-7.40 (m, 2H), 7.20 (td, 1H), 6.03 (s, 1H), 4.84(q, 1H), 4.16 (d, 1H), m/z: 609.2 4.12-4.02 (m, 2H), 3.86 (d, 1H), 3.81(d, 1H), 3.74-3.72 (m, 1H), 3.62-3.54 [M + H]⁺; (m, 1H), 3.35-3.33 (m,1H), 2.93-2.73 (m, 1H), 2.57-2.54 (m, 1H), 2.39-2.32 (m, 1H), 2.29-2.23(m, 1H), 1.89-1.82 (m, 1H), 1.67-1.58 (m, 1H), 1.25 (d, 3H), 1.12 (t,3H). Q4 ¹H NMR (600 MHz, DMSO-d₆): δ 9.91 (s, 1H), 8.04 (d, 1H), 7.94(d, 1H), MS (ESI, pos. ion) 7.44-7.41 (m, 2H), 7.18 (td, 1H), 6.06 (s,1H), 4.85 (q, 1H), 4.13-4.04 m/z: 595.2 (m, 3H), 3.92-3.86 (m, 1H),3.73-3.68 (m, 2H), 3.64-3.61 (m, 1H), 3.00 [M + H]⁺; (d, 1H), 2.91 (d,1H), 2.49-2.45 (m, 1H), 1.24 (d, 3H), 1.22 (d, 3H), 1.14 (t, 3H). Q5 ¹HNMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.76 (s, 1H), 8.03 (d, 1H), MS(ESI, pos. ion) 7.96 (d, 1H), 7.40-7.36 (m, 2H), 7.18 (td, 2H), 6.05 (s,1H), 4.86 (q, 1H), m/z: 623.2 4.15 (d, 1H), 4.10-4.01 (m, 2H), 3.84 (d,1H), 3.76-3.72 (m, 1H), 3.61-3.56 [M + H]⁺; (m, 1H), 3.55-3.46 (m, 1H),2.68 (d, 1H), 2.46-2.41 (m, 1H), 2.38-2.32 (m, 3H), 2.08-1.87 (m, 1H),1.79-1.71 (m, 1H), 1.24 (d, 3H), 1.21 (d, 3H), 1.16 (t, 3H). Q6 ¹H NMR(600 MHz, DMSO-d₆): δ 9.78 (s, 1H), 7.98 (d, 1H), 7.92 (d, 1H), MS (ESI,pos. ion) 7.46-7.41 (m, 2H), 7.21-7.18 (m, 1H), 6.06 (s, 1H), 4.87-4.77(m, 1H), 4.33 m/z: 601.2 (dd, 1H), 4.11-4.04 (m, 3H), 3.94-3.91 (m, 1H),3.52-3.50 (m, 1H), [M + H]⁺; 3.17-3.11 (m, 1H), 2.80-2.73 (m, 1H),2.47-2.42 (m, 1H), 1.24 (d, 3H), 1.14 (t, 3H). Q7 ¹H NMR (600 MHz,DMSO-d₆): δ 12.06 (s, 1H), 9.58 (s, 1H), 8.01 (d, 1H), MS (ESI, pos.ion) 7.94 (d, 1H), 7.46-7.41 (m, 2H), 7.20 (td, 1H), 6.08 (s, 1H), 4.87(q, 1H), m/z: 629.2 4.17-4.05 (m, 4H), 3.58-3.52 (m, 1H), 3.03-2.93 (m,2H), 2.63-2.53 (m, 1H), [M + H]⁺; 2.36-2.19 (m, 2H), 2.12-2.01 (m, 1H),1.95-1.88 (m, 1H), 1.59-1.52 (m, 1H), 1.25 (d, 3H), 1.14 (t, 3H). Q8 ¹HNMR (600 MHz, DMSO-d₆): δ 12.15 (s, 1H), 9.55 (s, 1H), 8.01 (d, 1H), MS(ESI, pos. ion) 7.95 (d, 1H), 7.47 (dd, 1H), 7.43 (dd, 1H), 7.19 (td,1H), 6.09 (s, 1H), 4.86 m/z: 629.2 (q, 1H), 4.17-4.05 (m, 4H), 3.48-3.43(m, 1H), 3.01-2.91 (m, 2H), 2.59-2.52 [M + H]⁺; (m, 1H), 2.40-2.23 (m,2H), 2.14-1.97 (m, 2H), 1.63-1.60 (m, 1H), 1.26 (d, 3H), 1.14 (t, 3H).

Step 2)(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added anhydrous ethanol (870 g) and lithium (2.43 g,0.35 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-((((R)-1-ethoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid (58.1 g, 0.1 mol) was added. The reaction mixture was allowed towarm up to 78° C. and stirred for 12 hours. After the reaction, themixture was cooled and concentrated. To the residue was added water(1100 g), the resulting mixture was extracted with ethyl acetate (1000mL). The organic layer was discarded. To the aqueous layer was addedethyl acetate (1280 mL), the mixture was adjusted to pH 3-6 withconcentrated hydrochloric acid. The organic layer was dried overanhydrous sodium sulfate and concentrated to give the product as ayellow solid (33.1 g, 65%).

MS (ESI, pos.ion) m/z: 509.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 13.00 (br, 1H), 9.95 (s, 1H), 8.02 (d, 1H),7.93 (d, 1H), 7.46-7.38 (m, 2H), 7.17 (td, 1H), 6.05 (s, 1H), 4.20 (d,1H), 4.05-4.02 (m, 1H), 3.97-3.91 (m, 3H), 3.81 (dd, 1H), 3.72-3.63 (m,2H), 3.58-3.53 (m, 1H), 3.08-3.05 (m, 1H), 2.42-2.38 (m, 1H), 1.06 (t,3H).

The compound X can be prepared under the reaction conditions shown intable 18 according to the procedure described in step 2 of Example 10.

TABLE 18 The reaction conditions for preparation of compound X

No. R³

The mole ratio of Lithium to compound Q; the amount of compound QReaction solvent Reaction temperature (° C.) Reaction time(h) Productcharacter Quality; yield (%) of product X1 ethyl

5; 6.4 g ethanol 78 2 yellow solid 3.38 g; 63 X2 ethyl

5; 6.4 g ethanol 78 2 yellow solid 3.33 g; 62 X3 ethyl

5; 6.4 g ethanol 78 2 yellow solid 2.63 g; 49 X4 ethyl

5; 6.26 g ethanol 78 12 yellow solid 3.77 g; 72 X5 ethyl

5; 6.54 g ethanol 78 2 yellow solid 2.48 g; 45 X6 ethyl

5; 6.3 g ethanol 78 12 yellow solid 3.07 g; 58 X7 ethyl

5; 6.6 g ethanol 78 2 yellow solid 2.73 g; 49 X8 ethyl

5; 6.6 g ethanol 78 2 yellow solid  2.9 g; 52 X9 methyl

5; 6.1 g methanol 64 18 yellow solid 3.47 g; 70 X10 methyl

5; 6.4 g methanol 64 6 yellow solid 3.14 g; 60 X11 methyl

5; 6.4 g methanol 64 4 yellow solid 3.09 g; 59 X12 methyl

5; 6.4 g methanol 64 8 yellow solid 2.41 g; 46 X13 methyl

5; 6.26 g methanol 64 18 yellow solid 3.51 g; 69 X14 methyl

5; 6.54 g methanol 64 5 yellow solid 2.31 g; 43 X15 methyl

5; 6.3 g methanol 64 12 yellow solid 2.83 g; 55 X16 methyl

5; 6.87 g methanol 64 6 yellow solid 2.55 g; 47 X17 methyl

5; 6.87 g methanol 64 6 yellow solid 2.66 g; 49

TABLE 18-1 The NMR and MS datum of compound X No. ¹H NMR MS X1 ¹H NMR(400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), MS (ESI,pos. ion) m/z: 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.05 (s, 1H), 3.96 (q,2H), 3.89-3.85 537.3 [M + H]⁺; (m, 3H), 3.59-3.46 (m, 2H), 2.80-2.74 (m,2H), 2.36-2.21 (m, 3H), 2.03-1.98 (m, 1H), 1.64-1.59 (m, 2H), 1.06 (t,3H). X2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 9.65 (s, 1H), 8.02(d, 1H), MS (ESI, pos. ion) m/z: 7.94 (d, 1H), 7.44-7.40 (m, 2H), 7.19(td, 1H), 6.06 (s, 1H), 3.97 (q, 2H), 536.9 [M + H]⁺; 3.92-3.82 (m, 3H),3.58-3.46 (m, 2H), 2.88 (d, 1H), 2.63 (d, 1H), 2.37-2.22 (m, 3H),2.08-1.99 (m, 1H), 1.72-1.65 (m, 2H), 1.05 (t, 3H). X3 ¹H NMR (400 MHz,DMSO-d₆): δ 12.13 (br, 1H), 9.81 (s, 1H), 8.02 MS (ESI, pos. ion) m/z:(d, 1H), 7.94 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.02 (s, 1H),4.20 537.2 [M + H]⁺; (d, 1H), 3.98 (q, 2H), 3.92 (d, 1H), 3.83-3.78 (m,1H), 3.75-3.72 (m, 1H), 3.62-3.58 (m, 1H), 3.37-3.33 (m, 1H), 2.79-2.75(m, 1H), 2.58-2.53 (m, 1H), 2.49-2.46 (m, 1H), 2.39-2.32 (m, 2H),1.89-1.83 (m, 1H), 1.66-1.58 (m, 1H), 1.06 (t, 3H). X4 ¹H NMR (600 MHz,DMSO-d₆): δ 13.00 (s, 1H), 9.78 (s, 1H), 8.03 (d, 1H), MS (ESI, pos.ion) m/z: 7.93 (d, 1H), 7.43-7.30 (m, 2H), 7.18 (td, 1H), 6.03 (s, 1H),4.06 (d, 1H), 523.2 [M + H]⁺; 3.95 (q, 2H), 3.90 (d, 1H), 3.74-3.69 (m,2H), 3.65-3.60 (m, 1H), 2.98 (d, 1H), 2.89 (d, 1H), 2.49-2.45 (m, 1H),1.21 (d, 3H), 1.04 (t, 3H). X5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s,1H), 9.75 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) m/z: 7.95 (d, 1H),7.42-7.36 (m, 2H), 7.15 (td, 1H), 6.06 (s, 1H), 4.15 (d, 1H), 551.2 [M +H]⁺; 4.02-3.91 (m, 2H), 3.86 (d, 1H), 3.75-3.73 (m, 1H), 3.59-3.54 (m,1H), 3.51-3.45 (m, 1H), 2.66 (d, 1H), 2.46-2.40 (m, 1H), 2.37-2.30 (m,3H), 2.03- 1.92 (m, 1H), 1.80-1.74 (m, 1H), 1.20 (d, 3H), 1.06 (t, 3H).X6 ¹H NMR (600 MHz, DMSO-d₆): δ 13.01 (br, 1H), 9.66 (s, 1H), 7.98 MS(ESI, pos. ion) m/z: (d, 1H), 7.91 (d, 1H), 7.45-7.41 (m, 2H), 7.19 (td,1H), 6.04 (s, 1H), 4.33 529.1 [M + H]⁺; (d, 1H), 4.08 (d, 1H), 4.05-4.02(m, 1H), 3.97 (q, 2H), 3.92-3.89 (m, 1H), 3.53-3.48 (m, 1H), 3.19-3.12(m, 1H), 2.82-2.72 (m, 1H), 1.05 (t, 3H). X7 ¹H NMR (400 MHz, DMSO-d₆):δ 12.08 (s, 1H), 9.52 (s, 1H), 7.99 (d, 1H), MS (ESI, pos. ion) m/z:7.92 (d, 1H), 7.44-7.40 (m, 2H), 7.19 (td, 1H), 6.03 (s, 1H), 4.13 (dd,2H), 556.9 [M + H]⁺; 3.97 (q, 2H), 3.60-3.52 (m, 1H), 3.06-2.96 (m, 2H),2.59-2.56 (m, 1H), 2.36-2.20 (m, 2H), 2.13-1.99 (m, 1H), 1.93-1.88 (m,1H), 1.57-1.44 (m, 1H), 1.05 (t, 3H). X8 ¹H NMR (400 MHz, DMSO-d₆): δ12.16 (br, 1H), 9.45 (s, 1H), 8.00 MS (ESI, pos. ion) m/z: (d, 1H), 7.94(d, 1H), 7.47-7.41 (m, 2H), 7.18 (td, 1H), 6.06 (s, 1H), 4.12 557.2 [M +H]⁺; (dd, 2H), 4.00-3.93 (m, 2H), 3.46-3.38 (m, 1H), 3.01-2.85 (m, 2H),2.60-2.53 (m, 1H), 2.40-2.23 (m, 2H), 2.15-1.99 (m, 2H), 1.66-1.56 (m,1H), 1.05 (t, 3H). X9 ¹H NMR (400 MHz, DMSO-d₆): δ 12.52 (br, 1H), 9.86(s, 1H), 8.03 MS (ESI, pos. ion) m/z: (d, 1H), 7.94 (d, 1H), 7.43-7.38(m, 2H), 7.16 (td, 1H), 6.04 (s, 1H), 4.24 494.9 [M + H]⁺; (d, 1H),4.06-3.97 (m, 2H), 3.84 (dd, 1H), 3.73-3.66 (m, 2H), 3.64-3.59 (m, 1H),3.51 (s, 3H), 3.10-3.06 (m, 1H), 2.43-2.39 (m, 1H). X10 ¹H NMR (400 MHz,DMSO-d₆): δ 12.12 (s, 1H), 9.71 (s, 1H), 8.03 (d, 1H), MS (ESI, pos.ion) m/z: 7.96 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.02 (s, 1H),3.94-3.82 522.9 [M + H]⁺; (m, 3H), 3.62-3.54 (m, 2H), 3.53 (s, 3H), 2.78(dd, 2H), 2.38-2.26 (m, 3H), 2.06-1.99 (m, 1H), 1.66-1.59 (m, 2H). X11¹H NMR (400 MHz, DMSO-d₆): δ 12.09 (br, 1H), 9.70 (s, 1H), 8.03 MS (ESI,pos. ion) m/z: (d, 1H), 7.94 (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H),6.04 (s, 1H), 3.95 523.2 [M + H]⁺; (d, 1H), 3.86-3.81 (m, 2H), 3.57-3.54(m, 1H), 3.52 (s, 3H), 3.50-3.47 (m, 1H), 2.87 (d, 1H), 2.62 (d, 1H),2.35-2.19 (m, 3H), 2.14-2.08 (m, 1H), 1.73-1.61 (m, 2H). X12 ¹H NMR (400MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), MS (ESI, pos.ion) m/z: 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.02 (s, 1H), 4.20 (d, 1H),3.93 (d, 1H), 523.1 [M + H]; 3.84-3.79 (m, 1H), 3.75-3.71 (m, 1H),3.62-3.56 (m, 1H), 3.52 (s, 3H), 3.48-3.41 (m, 1H), 3.05-2.87 (m, 1H),2.78-2.75 (m, 1H), 2.58-2.56 (m, 1H), 2.38-2.23 (m, 2H), 1.87-1.84 (m,1H), 1.66-1.58 (m, 1H). X13 ¹H NMR (600 MHz, DMSO-d₆): δ 13.01 (s, 1H),9.83 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) m/z: 7.93 (d, 1H),7.42-7.38 (m, 2H), 7.17 (td, 1H), 6.02 (s, 1H), 4.07 (d, 1H), 508.7 [M +H]⁺; 3.89 (d, 1H), 3.76-3.62 (m, 3H), 3.51 (s, 3H), 3.47-3.43 (m, 1H),2.98 (d, 1H), 2.89 (d, 1H), 1.20 (d, 3H). X14 ¹H NMR (400 MHz, DMSO-d₆):δ 12.11 (s, 1H), 9.76 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) m/z:7.96 (d, 1H), 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.01 (s, 1H), 4.16 (d,1H), 537.1 [M + H]⁺; 3.88 (d, 1H), 3.78-3.74 (m, 1H), 3.60-3.55 (m, 1H),3.53 (s, 3H), 3.50-3.46 (m, 1H), 2.68 (d, 1H), 2.48-2.42 (m, 1H),2.36-2.31 (m, 3H), 2.04-1.93 (m, 1H), 1.82-1.73 (m, 1H), 1.21 (d, 3H).X15 ¹H NMR (600 MHz, DMSO-d₆): δ 9.70 (br, 1H), 8.01 (d, 1H), 7.92 (d,1H), MS (ESI, pos. ion) m/z: 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.01 (s,1H), 4.31 (d, 1H), 4.09 (d, 1H), 515.1 [M + H]⁺; 3.94-3.89(m, 1H), 3.53(s, 3H), 3.48-3.44 (m, 1H), 3.23-3.07 (m, 2H), 2.84-2.75 (m, 1H). X16 ¹HNMR (400 MHz, DMSO-d₆): δ 12.07 (br, 1H), 9.55 (s, 1H), 7.99 MS (ESI,pos. ion) m/z: (d, 1H), 7.92 (d, 1H), 7.43-7.39 (m, 2H), 7.18 (td, 1H),6.03 (s, 1H), 4.15 543.0 [M + H]⁺; (d, 1H), 4.09 (d, 1H), 3.56-3.54 (m,1H), 3.53 (s, 3H), 3.05-2.95 (m, 2H), 2.48-2.46 (m, 1H), 2.36-2.17 (m,2H), 2.15-2.02 (m, 1H), 1.97-1.85 (m, 1H), 1.59-1.50 (m, 1H). X17 ¹H NMR(400 MHz, DMSO-d₆): δ 12.06 (br, 1H), 9.56 (s, 1H), 8.01 MS (ESI, pos.ion) m/z: (d, 1H), 7.94 (d, 1H), 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.05(s, 1H), 4.13 543.0 [M + H]⁺; (d, 1H), 4.09 (d, 1H), 3.57-3.54 (m, 1H),3.52 (s, 3H), 3.06-2.96 (m, 2H), 2.47-2.45 (m, 1H), 2.37-2.17 (m, 2H),2.16-2.02 (m, 1H), 1.98-1.85 (m, 1H), 1.60-1.51 (m, 1H).

Example 11: The Preparation of (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (360 g) and lithium (2.43 g,0.35 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(45.2 g, 0.1 mol) was added. The reaction mixture was stirred at 78° C.for 6 hours. After the reaction, the reaction mixture was cooled to 10°C., kept at 10° C. and stirred for 8 hours. The mixture was filtered.The filtrate was washed with anhydrous ethanol (45 g) and water (500 g)in turn, and then dried in vacuo at 60° C. for 8 hours to obtain theproduct as a yellow solid (23.6 g, 62%).

[a]_(D) ²⁵=−59.6 (c=0.3020 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 380.2 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.92 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H),7.41 (dd, 1H), 7.37 (dd, 1H), 7.19 (td, 1H), 6.00 (s, 1H), 3.93 (q, 2H),2.46 (s, 3H), 1.03 (t, 3H).

The compound T can be prepared under the reaction conditions shown intable 19 according to the procedure described in step 1 of Example 11.

TABLE 19 The reaction conditions for preparation of compound T

The mole ratio of Lithium The mass to compound ratio of (8); thereaction amount of solvent to Reaction Quality; compound Reactioncompound temperature Reaction Product yield (%) No. R³ (8) is 49.6 gsolvent (8) (° C.) time (h) character of product T1 ethyl 2.5 ethanol 1078 12 yellow 15.2 g; solid 40 T1 ethyl 3 ethanol 6 78 8 yellow 26.6 g;solid 70 T1 ethyl 4 ethanol 10 78 4 yellow 22 g; solid 58 T1 ethyl 5ethanol 20 78 24 yellow 17.1 g; solid 45 T1 ethyl 6 ethanol 30 78 12yellow 14.1 g; solid 37 T1 ethyl 8 ethanol 20 78 12 yellow 17.9 g; solid47 T2 methyl 3 methanol 3 64 20 yellow 20.9 g; solid 57 T2 methyl 3methanol 4 64 6 yellow 17.9 g; solid 49 T2 methyl 4 methanol 6 64 8yellow 11.7 g; solid 32

TABLE 19-1 The NMR, MS and specific rotation datum of the compound T No.¹H NMR MS specific rotation T1 ¹H NMR (600 MHz, DMSO-d₆): δ 9.92 (s,1H), 7.97 MS (ESI, pos. ion) m/z: [α]_(D) ²⁵ = −59.6 (c = (d, 1H), 7.90(d, 1H), 7.41 (dd, 1H), 7.37 (dd, 1H), 7.19 380.2 [M + H]⁺; 0.3020 g/100(td, 1H), 6.00 (s, 1H), 3.93 (q, 2H), 2.46 (s, 3H), 1.03 mL, MeOH); (t,3H). T2 ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (d, 1H), 7.68 MS (ESI, pos.ion) m/z: [α]_(D) ²⁵ = −81.49 (c = (d, 1H), 7.36 (dd, 1H), 7.29 (dd,1H), 7.11 (td, 1H), 5.90 366.1 [M + H]⁺; 0.5031 g/100 (s, 1H), 3.41 (s,3H), 2.34 (s, 3H). mL, MeOH);

Step 2) (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-bromomethyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a dry flask were added (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(38 g, 0.1 mol) and CCl₄ (760 g), followed by NBS (19.6 g, 0.11 mol) at70° C. The mixture was stirred for 30 min and cooled, and then filtered.The filtrate was concentrated to obtain a yellow solid (37.6 g, 82%).

MS (ESI, pos.ion) m/z: 457.9 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.67 (s, 1H), 8.01 (d, 1H), 7.97 (br, 1H),7.44-7.41 (m, 2H), 7.22 (td, 1H), 5.99 (s, 1H), 4.83 (br, 2H), 4.02 (q,2H), 1.07 (t, 3H).

The compound W can be prepared under the reaction conditions shown intable 20 according to the procedure described in step 2 of Example 11.

TABLE 20 The reaction conditions for preparation of compound W

The The mole mass ratio of ratio NBS to of com- reac- pound tion T; thesolvent Reac- Qual- amount Reac- to tion Pro- ity; of com- tion com-tempe- duct yield pound sol- pound rature charac- (%) of No. R³ T vent(W) (° C.) ter product W1 ethyl 1.0; DCM 10 39 yellow 37.2 g; 38 g solid81 W1 ethyl 1.0; CHCl₃ 20 61 yellow 35.8 g; 38 g solid 78 W1 ethyl 1.1;CCl₄ 30 76 yellow 38.6 g; 38 g solid 84 W2 methyl 1.0; DCM 10 39 yellow32 g; 36.6 g solid 72 W2 methyl 1.1; CHCl₃ 20 61 yellow 32.5 g; 36.6 gsolid 73 W2 methyl 1.1; CCl₄ 30 76 yellow 36.5 g; 36.6 g solid 82

TABLE 20-1 The NMR and MS datum of compound W No. ¹H NMR MS W1 ¹H NMR(400 MHz, DMSO-d₆): δ 9.62 (s, 1H), 8.01 (d, 1H), 7.92 (d, 1H), MS (ESI,pos. ion) 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.04 (s, 1H), 4.94 (d, 1H),4.62 (d, 1H), 4.15 m/z: 457.9 (q, 2H), 1.12 (t, 3H). [M + H]⁺; W2 ¹H NMR(600 MHz, DMSO-d₆): δ 8.02 (d, 1H), 7.96 (br, 1H), 7.46-7.40 MS (ESI,pos. ion) (m, 2H), 7.22 (td, 1H), 5.98 (s, 1H), 4.83 (br, 2H), 3.57 (s,3H). m/z: 445.6 [M + H]⁺;

Step 3) (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(45.9 g, 0.1 mol), anhydrous ethanol (275 g) and morpholine (34.8 g, 0.4mol). The mixture was stirred at 25° C. under nitrogen atmosphere for 6hours. After the reaction, the mixture was concentrated. To the residuewas added ethyl acetate (500 g), the resulting mixture was washed withwater (250 mL×2). The organic layer was concentrated to give the productas tawny oil (35.8 g, 77%)

MS (ESI, pos.ion) m/z: 465.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.00 (d, 1H), 7.91 (d, 1H),7.40-7.37 (m, 2H), 7.15 (td, 1H), 6.03 (s, 1H), 3.94 (q, 2H), 3.88 (dd,2H), 3.65 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).

The compound U can be prepared under the reaction conditions shown intable 21 according to the procedure described in step 3 of Example 11.

TABLE 21 The reaction conditions for preparation of compound U

The mole ratio The mass of compound (6) ratio of to compound W; reactionReaction Quality; the amount of Reaction solvent to temperature ReactionProduct yield (%) of No. R³ compound W solvent compound (J) (° C.) time(h) character product U1 ethyl 2; 45.9 g ethanol 20 25  2 tawny oil 34g; 73 U1 ethyl 3; 45.9 g acetone 10 40 10 tawny oil 36.3 g; 78 U1 ethyl4; 45.9 g methanol 10 30  6 tawny oil 33.5 g; 72 U1 ethyl 5; 45.9 gethyl acetate 20 50 24 tawny oil 34.4 g; 74 U1 ethyl 6; 45.9 g DCM  8 39 6 tawny oil 33 g; 71 U1 ethyl 3; 45.9 g DMF  4 60  1 tawny oil 31.6 g;68 U1 ethyl 4; 45.9 g THF  6 50  8 tawny oil 33.5 g; 72 U2 methyl 2;44.5 g ethanol 20 25  2 tawny oil 33.8 g; 75 U2 methyl 3; 44.5 g acetone10 40 10 tawny oil 32.4 g; 72 U2 methyl 4; 44.5 g methanol 10 30  6tawny oil 34.6 g; 77 U2 methyl 5; 44.5 g ethyl acetate 20 50 24 tawnyoil 33.3 g; 74 U2 methyl 6; 44.5 g DCM  8 39  6 tawny oil 30.2 g; 67 U2methyl 3; 44.5 g DMF  4 60  1 tawny oil 32 g; 71 U2 methyl 4; 44.5 g THF 6 50  8 tawny oil 30.6 g; 68

TABLE 21-1 The NMR and MS datum of compound U No. ¹H NMR MS U1 ¹H NMR(400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.00 (d, 1H), 7.91 (d, 1H), MS (ESI,pos. ion) 7.40-7.37 (m, 2H), 7.15 (td, 1H), 6.03 (s, 1H), 3.94 (q, 2H),3.88 (dd, 2H), 3.65 m/z: 465.2 (br, 4H), 2.56 (br, 4H), 1.05 (t, 3H).[M + H]⁺; U2 ¹H NMR (600 MHz, DMSO-d₆): δ 9.72 (s, 1H), 8.03 (d, 1H),7.94 MS (ESI, pos. ion) (d, 1H), 7.43-7.38 (m, 2H), 7.17 (td, 1H), 6.05(s, 1H), 3.93 (dd, 2H), 3.68 (br, 4H), m/z: 450.8 3.53 (s, 3H), 2.56(br, 4H). [M + H]⁺;

Example 12: The Preparation of(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added (R)-ethyl4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(4.59 g, 10 mmol), (S)-morpholine-3-carboxylic acid (1.31 g, 10 mmol),potassium carbonate (2.76 g, 20 mmol) and ethanol (90 mL). The mixturewas stirred at 30° C. under nitrogen atmosphere for 12 hours. After thereaction, the mixture was filtered. The filtrate was concentrated. Tothe residue was added water (100 mL), the resulting mixture wasextracted with ethyl acetate (100 mL). The organic layer was discarded.To the aqueous layer was added ethyl acetate (100 mL), and the mixturewas adjusted to pH 3-6 with concentrated hydrochloric acid. The organiclayer was dried over anhydrous sodium sulfate and concentrated to givethe product as a yellow solid (3.96 g, 78%).

MS (ESI, pos.ion) m/z: 509.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 13.00 (br, 1H), 9.95 (s, 1H), 8.02 (d, 1H),7.93 (d, 1H), 7.46-7.38 (m, 2H), 7.17 (td, 1H), 6.05 (s, 1H), 4.20 (d,1H), 4.05-4.02 (m, 1H), 3.97-3.91 (m, 3H), 3.81 (dd, 1H), 3.72-3.63 (m,2H), 3.58-3.53 (m, 1H), 3.08-3.05 (m, 1H), 2.42-2.38 (m, 1H), 1.06 (t,3H).

The compound X can be prepared under the reaction conditions shown intable 22 according to the procedure described Example 12.

TABLE 22 The reaction conditions for preparation of compound X

No. R³

The mole ratio of compound W to compound (VI); the amount of compound WReaction solvent The mass ratio of reaction solvent to compound (W)Reaction temperature (° C.) Reaction time (h) Product character Quality;yield (%) of product X1 ethyl

1; 4.59 g ethanol 20 30  4 yellow solid 3.65 g; 68 X2 ethyl

1; 4.59 g ethanol 15 30  6 yellow solid 3.6 g; 67 X3 ethyl

1; 4.59 g ethanol 10 30 12 yellow solid 2.31 g; 43 X4 ethyl

1; 4.59 g ethanol  4 30 24 yellow solid 4.1 g; 78 X5 ethyl

1; 4.59 g ethanol 12 30 16 yellow solid 2.76 g; 50 X6 ethyl

1; 4.59 g ethanol 20 30 24 yellow solid 3.97 g; 75 X7 ethyl

1; 4.59 g ethanol 10 30 12 yellow solid 3.45 g; 62 X8 ethyl

1; 4.59 g ethanol 15 30 18 yellow solid 3.4 g; 61 X9 methyl

1; 4.45 g ethanol  6 30 24 yellow solid 3.47 g; 70 X10 methyl

1; 4.45 g ethanol 10 30 12 yellow solid 3.45 g; 66 X11 methyl

1; 4.45 g ethanol 20 30 16 yellow solid 3.29 g; 63 X12 methyl

1; 4.45 g ethanol 15 30 20 yellow solid 2.2 g; 42 X13 methyl

1; 4.45 g ethanol 30 30  2 yellow solid 3.82 g; 75 X14 methyl

1; 4.45 g ethanol  8 30 10 yellow solid 2.47 g; 46 X15 methyl

1; 4.45 g ethanol 15 30 16 yellow solid 3.71 g; 72 X16 methyl

1; 4.45 g ethanol 10 30  8 yellow solid 3.2 g; 59 X17 methyl

1; 4.45 g ethanol 20 30  8 yellow solid 3.15 g; 58

TABLE 22-1 The NMR and MS datum of compound X No. ¹H NMR MS X1 ¹H NMR(400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), MS (ESI,pos. ion) 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.05 (s, 1H), 3.96 (q, 2H),3.89-3.85 (m, 3H), m/z: 537.3 3.59-3.46 (m, 2H), 2.80-2.74 (m, 2H),2.36-2.21 (m, 3H), 2.03-1.98 (m, 1H), [M + H]⁺; 1.64-1.59 (m, 2H), 1.06(t, 3H). X2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 9.65 (s, 1H),8.02 (d, 1H), 7.94 MS (ESI, pos. ion) (d, 1H), 7.44-7.40 (m, 2H), 7.19(td, 1H), 6.06 (s, 1H), 3.97 (q, 2H), 3.92-3.82 m/z: 536.9 (m, 3H),3.58-3.46 (m, 2H), 2.88 (d, 1H), 2.63 (d, 1H), 2.37-2.22 [M + H]⁺; (m,3H), 2.08-1.99 (m, 1H), 1.72-1.65 (m, 2H), 1.05 (t, 3H). X3 ¹H NMR (400MHz, DMSO-d₆): δ 12.13 (br, 1H), 9.81 (s, 1H), 8.02 (d, 1H), 7.94 MS(ESI, pos. ion) (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.02 (s, 1H),4.20 (d, 1H), 3.98 (q, 2H), m/z: 537.2 3.92 (d, 1H), 3.83-3.78 (m, 1H),3.75-3.72 (m, 1H), 3.62-3.58 (m, 1H), 3.37-3.33 [M + H]⁺; (m, 1H),2.79-2.75 (m, 1H), 2.58-2.53 (m, 1H), 2.49-2.46 (m, 1H), 2.39-2.32 (m,2H), 1.89-1.83 (m, 1H), 1.66-1.58 (m, 1H), 1.06 (t, 3H). X4 ¹H NMR (600MHz, DMSO-d₆): δ 13.00 (s, 1H), 9.78 (s, 1H), 8.03 (d, 1H), 7.93 MS(ESI, pos. ion) (d, 1H), 7.43-7.30 (m, 2H), 7.18 (td, 1H), 6.03 (s, 1H),4.06 (d, 1H), 3.95 (q, 2H), m/z: 523.2 3.90 (d, 1H), 3.74-3.69 (m, 2H),3.65-3.60 (m, 1H), 2.98 (d, 1H), 2.89 (d, 1H), [M + H]⁺; 2.49-2.45 (m,1H), 1.21 (d, 3H), 1.04 (t, 3H). X5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.12(s, 1H), 9.75 (s, 1H), 8.02 (d, 1H), 7.95 MS (ESI, pos. ion) (d, 1H),7.42-7.36 (m, 2H), 7.15 (td, 1H), 6.06 (s, 1H), 4.15 (d, 1H), 4.02-3.91m/z: 551.2 (m, 2H), 3.86 (d, 1H), 3.75-3.73 (m, 1H), 3.59-3.54 (m, 1H),3.51-3.45 (m, 1H), [M + H]⁺; 2.66 (d, 1H), 2.46-2.40 (m, 1H), 2.37-2.30(m, 3H), 2.03 -1.92 (m, 1H), 1.80-1.74 (m, 1H), 1.20 (d, 3H), 1.06 (t,3H). X6 ¹H NMR (600 MHz, DMSO-d₆): δ 13.01 (br, 1H), 9.66 (s, 1H), 7.98(d, 1H), 7.91 MS (ESI, pos. ion) (d, 1H), 7.45-7.41 (m, 2H), 7.19 (td,1H), 6.04 (s, 1H), 4.33 (d, 1H), 4.08 (d, 1H), m/z: 529.1 4.05-4.02 (m,1H), 3.97 (q, 2H), 3.92-3.89 (m, 1H), 3.53-3.48 (m, 1H), 3.19-3.12 [M +H]⁺; (m, 1H), 2.82-2.72 (m, 1H), 1.05 (t, 3H). X7 ¹H NMR (400 MHz,DMSO-d₆): δ 12.08 (s, 1H), 9.52 (s, 1H), 7.99 (d, 1H), 7.92 MS (ESI,pos. ion) (d, 1H), 7.44-7.40 (m, 2H), 7.19 (td, 1H), 6.03 (s, 1H), 4.13(dd, 2H), 3.97 (q, 2H), m/z: 556.9 3.60-3.52 (m, 1H), 3.06-2.96 (m, 2H),2.59-2.56 (m, 1H), 2.36-2.20 (m, 2H), [M + H]⁺; 2.13-1.99 (m, 1H),1.93-1.88 (m, 1H), 1.57-1.44 (m, 1H), 1.05 (t, 3H). X8 ¹H NMR (400 MHz,DMSO-d₆): δ 12.16 (br, 1H), 9.45 (s, 1H), 8.00 (d, 1H), 7.94 MS (ESI,pos. ion) (d, 1H), 7.47-7.41 (m, 2H), 7.18 (td, 1H), 6.06 (s, 1H), 4.12(dd, 2H), 4.00-3.93 m/z: 557.2 (m, 2H), 3.46-3.38 (m, 1H), 3.01-2.85 (m,2H), 2.60-2.53 (m, 1H), 2.40-2.23 [M + H]⁺; (m, 2H), 2.15-1.99 (m, 2H),1.66-1.56 (m, 1H), 1.05 (t, 3H). X9 ¹H NMR (400 MHz, DMSO-d₆): δ 12.52(br, 1H), 9.86 (s, 1H), 8.03 (d, 1H), 7.94 MS (ESI, pos. ion) (d, 1H),7.43-7.38 (m, 2H), 7.16 (td, 1H), 6.04 (s, 1H), 4.24 (d, 1H), 4.06-3.97m/z: 494.9 (m, 2H), 3.84 (dd, 1H), 3.73-3.66 (m, 2H), 3.64-3.59 (m, 1H),3.51 (s, 3H), 3.10- [M + H]⁺; 3.06 (m, 1H), 2.43-2.39 (m, 1H). X10 ¹HNMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.71 (s, 1H), 8.03 (d, 1H),7.96 MS (ESI, pos. ion) (d, 1H), 7.44-7.38 (m, 2H), 7.18 (td, 1H), 6.02(s, 1H), 3.94-3.82 (m, 3H), m/z: 522.9 3.62-3.54 (m, 2H), 3.53 (s, 3H),2.78 (dd, 2H), 2.38-2.26 (m, 3H), 2.06-1.99 [M + H]⁺; (m, 1H), 1.66-1.59(m, 2H). X11 ¹H NMR (400 MHz, DMSO-d₆): δ 12.09 (br, 1H), 9.70 (s, 1H),8.03 (d, 1H), 7.94 MS (ESI, pos. ion) (d, 1H), 7.44-7.38 (m, 2H), 7.18(td, 1H), 6.04 (s, 1H), 3.95 (d, 1H), 3.86-3.81 m/z: 523.2 (m, 2H),3.57-3.54 (m, 1H), 3.52 (s, 3H), 3.50-3.47 (m, 1H), 2.87 (d, 1H), 2.62[M + H]⁺; (d, 1H), 2.35-2.19 (m, 3H), 2.14-2.08 (m, 1H), 1.73-1.61 (m,2H). X12 ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.03 (d, 1H), 7.94(d, 1H), MS (ESI, pos. ion) 7.44-7.40 (m, 2H), 7.16 (td, 1H), 6.02 (s,1H), 4.20 (d, 1H), 3.93 (d, 1H), 3.84-3.79 m/z: 523.1 (m, 1H), 3.75-3.71(m, 1H), 3.62-3.56 (m, 1H), 3.52 (s, 3H), 3.48-3.41 (m, 1H), [M + H]⁺;3.05-2.87 (m, 1H), 2.78-2.75 (m, 1H), 2.58-2.56 (m, 1H), 2.38-2.23 (m,2H), 1.87-1.84 (m, 1H), 1.66-1.58 (m, 1H). X13 ¹H NMR (600 MHz,DMSO-d₆): δ 13.01 (s, 1H), 9.83 (s, 1H), 8.02 (d, 1H), 7.93 MS (ESI,pos. ion) (d, 1H), 7.42-7.38 (m, 2H), 7.17 (td, 1H), 6.02 (s, 1H), 4.07(d, 1H), 3.89 (d, 1H), m/z: 508.7 3.76-3.62 (m, 3H), 3.51 (s, 3H),3.47-3.43 (m, 1H), 2.98 (d, 1H), 2.89 (d, 1H), 1.20 [M + H]⁺; (d, 3H).X14 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 9.76 (s, 1H), 8.02 (d,1H), 7.96 MS (ESI, pos. ion) (d, 1H), 7.44-7.40 (m, 2H), 7.16 (td, 1H),6.01 (s, 1H), 4.16 (d, 1H), 3.88 (d, 1H), m/z: 537.1 3.78-3.74 (m, 1H),3.60-3.55 (m, 1H), 3.53 (s, 3H), 3.50-3.46 (m, 1H), 2.68 [M + H]⁺; (d,1H), 2.48-2.42 (m, 1H), 2.36-2.31 (m, 3H), 2.04 -1.93 (m, 1H), 1.82-1.73(m, 1H), 1.21 (d, 3H). X15 ¹H NMR (600 MHz, DMSO-d₆): δ 9.70 (br, 1H),8.01 (d, 1H), 7.92 (d, 1H), MS (ESI, pos. ion) 7.44-7.38 (m, 2H), 7.18(td, 1H), 6.01 (s, 1H), 4.31 (d, 1H), 4.09 (d, 1H), 3.94-3.89 m/z: 515.1(m, 1H), 3.53 (s, 3H), 3.48-3.44 (m, 1H), 3.23-3.07 (m, 2H), 2.84-2.75(m, 1H). [M + H]⁺; X16 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (br, 1H), 9.55(s, 1H), 7.99 (d, 1H), 7.92 MS (ESI, pos. ion) (d, 1H), 7.43-7.39 (m,2H), 7.18 (td, 1H), 6.03 (s, 1H), 4.15 (d, 1H), 4.09 (d, 1H), m/z: 543.03.56-3.54 (m, 1H), 3.53 (s, 3H), 3.05-2.95 (m, 2H), 2.48-2.46 (m, 1H),2.36-2.17 [M + H]⁺; (m, 2H), 2.15-2.02 (m, 1H), 1.97-1.85 (m, 1H),1.59-1.50 (m, 1H). X17 ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (br, 1H), 9.56(s, 1H), 8.01 (d, 1H), 7.94 MS (ESI, pos. ion) (d, 1H), 7.44-7.40 (m,2H), 7.16 (td, 1H), 6.05 (s, 1H), 4.13 (d, 1H), 4.09 (d, 1H), m/z: 543.03.57-3.54 (m, 1H), 3.52 (s, 3H), 3.06-2.96 (m, 2H), 2.47-2.45 (m, 1H),2.37-2.17 [M + H]⁺; (m, 2H), 2.16-2.02 (m, 1H), 1.98-1.85 (m, 1H),1.60-1.51 (m, 1H).

Example 13: The Preparation of (R)-ethyl4-(2,4-dichlorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Method One:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2,4-dichlorobenzaldehyde (17.5 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (107 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, themixture was cooled to 30° C., kept at 30° C. and stirred for 6 hours.The resulting mixture was filtered. The filter cake was washed withwater (330 mL) and dried in vacuo at 60° C. for 8 hours to obtain thecrude product. To the crude product was added n-propanol (82 g). Themixture was heated until dissolved completely, cooled to 30° C., andthen kept at 30° C., stirred and crystallized for 5 hours. The resultingmixture was filtered. The filter cake was dried in vacuo at 60° C. for 8hours to obtain the product as a yellow solid (12.1 g, 25.9%).

[a]_(D) ²⁵=−74.42 (c=0.3037 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 467.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.07 (s, 1H), 7.98 (d, 1H), 7.91 (d, 1H),7.59 (d, 1H), 7.41 (dd, 1H), 7.36 (d, H), 6.03 (s, 1H), 4.83 (q, 1H),4.12-4.03 (m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.13 (t, 3H).

The compound 10 can be prepared under the reaction conditions shown intable 23 by using method one described in step 1 of Example 13.

TABLE 23 The reaction conditions

(1):(9):(3):(4) The The (mol); mass mass the ratio of ratio of amountreaction Reac- Cool- recrystal- Crystal- of solvent tion Reac- ing Cool-lization lization Quality; compound to temper- tion temper- ingRecrystal- solvent temper- Crystal- yield (1) is Reaction compound aturetime ature time lization to ature lization (%) of No. 16.4 g solvent (1)(° C.) (h) (° C.) (h) solvent compound (1) (° C.) time (h) product 11:1:2:1 — — 78 12 40 6 ethanol 20 5 6 9.8 g; 20.9 2 1:1:1:1 ethanol 1 7812 40 6 ethanol 15 15 8 10.6 g; 22.6 3 1:1:1:1 ethanol 4.5 25 72 25 —ethanol 5 0 6 9.3 g; 19.8 4 1:1:1:1 ethanol 20 60 24 −10 12 ethanol 6 254 11.1 g; 23.7 5 1:1:1:1 ethanol 80 78 12 −40 24 ethanol 6 25 6 10.7 g;22.8 6 1:1:1:1 DMF 4.5 154 1 −20 6 i- 6 20 4 7.3 g; propanol 15.7 71:1:1:1 n- 4.5 100 2 −5 10 n- 4.5 25 4 9.1 g; butanol butanol 19.4 81:1:1:1 n- 4.5 80 12 30 6 n- 4 40 10 12.8 g; propanol propanol 27.4 91:1:1:1 i- 4.5 82 12 25 1 i- 5 25 1 13.2 g; propanol propanol 28.3 101:1:1:1 t- 5 82 12 30 6 t- 5 25 6 13.3 g; butanol butanol 28.5Method Two

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2,4-dichlorobenzaldehyde (17.5 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (107 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, thereaction mixture was cooled to 30° C., kept at 30° C. and stirred for 3hours. The mixture was filtered. The filtrate was washed with ethanol(50 g) and water (330 mL) in turn, and then dried in vacuo at 60° C. for8 hours to obtain the product as a yellow solid (14.4 g, 30.8%).

[a]_(D) ²⁵=−74.42 (c=0.3037 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 467.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.07 (s, 1H), 7.98 (d, 1H), 7.91 (d, 1H),7.59 (d, 1H), 7.41 (dd, 1H), 7.36 (d, 1H), 6.03 (s, 1H), 4.83 (q, 1H),4.12-4.03 (m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.13 (t, 3H).

The compound 10 can be prepared under the reaction conditions shown intable 24 by using method two described in step 1 of Example 13.

TABLE 24 The reaction conditions

(1):(9):(3):(4) The The (mol); mass mass the ratio of ratio of amountreaction Reac- Cool- washing Wash- of solvent tion Reac- ing Cool-solvent ing Quality; compound to temper- tion temper- ing to temper-yield (%) (1) is Reaction compound ature time ature time Washingcompound ature of No. 16.4 g solvent (1) (° C.) (h) (° C.) (h) solvent(1) (° C.) product 1 1:1:2:1 — — 78 12 40 6 ethanol 10 25 10.9 g; 23.3 21:1:1:1 ethanol 1 78 12 40 6 ethanol 8 25 11.6 g; 24.7 3 1:1:1:1 ethanol5 25 72 25 — ethanol 1 25 10.2 g; 21.8 4 1:1:1:1 ethanol 9 78 12 25 4 —— — 12.4 g; 26.6 5 1:1:1:1 ethanol 20 60 24 −10 6 ethanol 3.5 25 11.7 g;24.9 6 1:1:1:1 ethanol 80 78 12 −30 24 ethanol 5 25 11.6 g; 24.7 71:1:1:1 DMF 4.5 154 1 −20 6 i- 3 0 7.9 g; propanol 16.9 8 1:1:1:1 n- 4.5100 2 −5 7 n- 3.5 25 10 g; butanol butanol 21.4 9 1:1:1:1 n- 4.5 80 1230 6 n- 3 25 13.9 g; propanol propanol 29.6 10 1:1:1:1 i- 4.5 82 12 25 1i- 2 30 14.3 g; propanol propanol 30.5 11 1:1:1:1 t- 5 82 12 30 6 t- 3.525 13.9 g; butanol butanol 29.8Method Three:

To a flask were added 2-thiazolecarboxamidine hydrochloride (16.4 g, 0.1mol), 2,4-dichlorobenzaldehyde (17.5 g, 0.1 mol),(R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol),anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (107 g) in turn.The mixture was stirred at 78° C. for 16 hours. After the reaction, themixture was cooled to 30° C., kept at 30° C. and stirred for 3 hours.The resulting mixture was filtered. The filter cake was washed withwater (330 mL) and dried in vacuo at 60° C. for 8 hours to obtain thecrude product. The crude product was triturated with i-propanol (82 g)at 30° C. for 5 hours and filtered. The filter cake was dried in vacuoat 60° C. for 8 hours to obtain the product as a yellow solid (12.9 g,27.5%).

[a]_(D) ²⁵=−74.42 (c=0.3037 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 467.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 10.07 (s, 1H), 7.98 (d, 1H), 7.91 (d, 1H),7.59 (d, 1H), 7.41 (dd, 1H), 7.36 (d, 1H), 6.03 (s, 1H), 4.83 (q, 1H),4.12-4.03 (m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.13 (t, 3H).

The compound 10 can be prepared under the reaction conditions shown intable 25 by using method three described in step 1 of Example 13.

TABLE 25 The reaction conditions

(1):(9):(3):(4) The The (mol); mass mass the ratio of ratio of amountreaction Reac- Cool- tritu- Tritu- of solvent tion Reac- ing Cool-ration ration Tritu- Quality; compound to temper- tion temper- ingTritu- solvent temper- ration yield (%) (1) is Reaction compound aturetime ature time ration to com- ature time of No. 16.4 g solvent (1) (°C.) (h) (° C.) (h) solvent pound (1) (° C.) (h) product 1 1:1:2:1 — — 7812 40 6 ethanol 12 25 10 10.5 g; 22.4 2 1:1:1:1 ethanol 1 78 12 40 6ethanol 8 25 4 11 g; 23.5 3 1:1:1:1 ethanol 5 25 72 25 — ethanol 3 40 39.8 g; 20.9 4 1:1:1:1 ethanol 20 60 24 −10 12 ethanol 5 25 2 11.4 g;24.3 5 1:1:1:1 ethanol 80 78 12 −40 24 ethanol 4 25 3 10.7 g; 22.9 61:1:1:1 DMF 4.5 154 1 −20 6 i- 4.5 25 2 7.6 g; propanol 16.3 7 1:1:1:1n- 4.5 100 2 −5 10 n- 4 25 3 9.6 g; butanol butanol 20.6 8 1:1:1:1 n-4.5 80 12 30 6 n- 5 0 2 13.3 g; propanol propanol 28.5 9 1:1:1:1 i- 4.582 12 25 1 i- 6 5 4 13.7 g; propanol propanol 29.2 10 1:1:1:1 t- 5 82 1230 6 t- 4 25 4 13.6 g; butanol butanol 29.1

Step 2) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-bromomethyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(46.8 g, 0.1 mol) and tetrachloromethane (936 g). The mixture was heatedat 76° C., NBS was added (19.6 g, 0.11 mol), and then the reactionmixture was stirred for 30 min. After the reaction, the reaction mixturewas cooled and concentrated. To the residue was added ethanol (234 g).The resulting mixture was cooled to 0° C., kept at 0° C. and stirred.After solid was precipitated out completely, the mixture was filtered.The filter cake was washed with ethanol (47 g) and dried in vacuo at 60°C. for 6 hours to obtain the product as a yellow solid (30.1 g, 55%).

MS (ESI, pos.ion) m/z: 548.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 8.01 (d, 1H), 7.96 (d, 1H),7.59 (br, 2H), 7.39 (br, 2H), 6.01 (s, 1H), 4.96 (q, 1H), 4.88-4.79 (m,2H), 4.14-4.03 (m, 2H), 1.26 (d, 3H), 1.12 (t, 3H).

The compound A3 can be prepared under the reaction conditions shown intable 26 according to the procedure described in step 2 of Example 13

TABLE 26 The reaction conditions

The mass The mass Compound ratio of ratio of the (10)/NBS(mol) reactionThe additional the amount of solvent to Reaction solvent solvent toQuality; compound (10) is Reaction compound temperature added tocompound yield (%) No. 46.8 g solvent (10) (° C.) the residue (10) ofproduct 1 1/1.1  DCM 30 39 i-propanol 7 28.9 g; 53 2 1/1.05 DCM 10 39ethanol 5 31.2 g; 57 3 1/1.15 CHCl₃ 20 61 n-propanol 6 30.6 g; 56 41/1.1  CCl₄ 20 76 ethanol 5 32.3 g; 59

Step 3) (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(54.7 g, 0.1 mol), i-propanol (273 g) and morpholine (34.8 g, 0.4 mol).The mixture was stirred at 55° C. for 4 hours. After the reaction, themixture was cooled to 0° C., kept at this temperature and stirred. Afterthe solid precipitated out completely, the mixture was filtered. Thefilter cake was washed with i-propanol (55 g) followed by water (550 g),and then dried in vacuo at 60° C. for 8 hours to obtain the product as ayellowish solid (33.7 g, 61%).

MS (ESI, pos.ion) m/z: 553.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.01 (d, 1H), 7.96 (d, 1H),7.59 (br, 1H), 7.38 (br, 2H), 6.05 (s, 1H), 4.86 (q, 1H), 4.14-4.06 (m,2H), 3.92 (dd, 2H), 3.67 (br, 4H), 2.56 (br, 4H), 1.24 (d, 3H), 1.13 (t,3H).

Step 4) (R)-ethyl4-(2,4-dichlorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (415 g) and lithium (1.74 g,0.25 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then a solution of(R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(55.3 g, 0.1 mol) in ethanol (415 g) was added. The reaction mixture wasstirred at 78° C. for 1.5 hours. After the reaction, the reactionmixture was cooled and concentrated. To the residue was added ethylacetate (540 g). The mixture was washed with water (250 g×2). Theorganic layer was concentrated to obtain the product as yellow thick oil(34.6 g, 72%).

MS (ESI, pos.ion) m/z: 480.7 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H),7.60 (s, 1H), 7.39 (s, 2H), 6.06 (s, 1H), 3.97 (q, 2H), 3.92 (dd, 2H),3.67 (br, 4H), 2.56 (br, 4H), 1.06 (t, 3H).

Example 14: The Preparation of (R)-methyl4-(2,4-dichlorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous methanol (830 g) and lithium (1.74 g,0.25 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(55.3 g, 0.1 mol) was added. The reaction mixture was stirred at 60° C.for 1.5 hours. After the reaction, the reaction mixture was cooled andconcentrated. To the residue was added ethyl acetate (550 g). Themixture was washed with water (250 g×2). The combined organic layerswere concentrated to obtain the product as yellow thick oil (32.2 g,69%).

MS (ESI, pos.ion) m/z: 467.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ 9.73 (s, 1H), 7.87 (d, 1H), 7.47 (d, 1H),7.42 (d, 1H), 7.24 (d, 1H), 7.18 (dd, 1H), 6.21 (s, 1H), 4.02 (d, 1H),3.89 (d, 1H), 3.85 (t, 4H), 3.62 (s, 3H), 2.65 (t, 4H).

Example 15: The Preparation of(S)-4-(((R)-6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

Step 1)(S)-4-(((R)-6-(2,4-dichlorophenyl)-5-((((R)-1-ethoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(54.7 g, 0.1 mol), ethanol (820 g), (S)-morpholine-3-carboxylic acid(13.1 g, 0.1 mol) and potassium carbonate (27.6 g, 0.2 mol) in turn. Themixture was stirred at 30° C. for 12 hours. After the reaction, themixture was filtered. The filtrate was concentrated. To the residue wasadded water (820 g), the resulting mixture was extracted with ethylacetate (820 mL). The organic layer was discarded. To the aqueous layerwas added ethyl acetate (900 mL), the mixture was adjusted to pH 3-6with concentrated hydrochloric acid. The organic layer was dried overanhydrous sodium sulfate and concentrated to give the product as ayellow solid (43.6 g, 73%).

MS (ESI, pos.ion) m/z: 596.6 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 12.87 (br, 1H), 9.93 (s, 1H), 8.04 (d, 1H),7.96 (d, 1H), 7.60 (d, 1H), 7.43-7.37 (m, 2H), 6.09 (s, 1H), 4.85 (q,1H), 4.22 (d, 1H), 4.13-3.99 (m, 4H), 3.85 (dd, 1H), 3.74-3.61 (m, 3H),3.12-3.04 (m, 1H), 2.43-2.38 (m, 1H), 1.24 (d, 3H), 1.13 (t, 3H).

The compound H can be prepared under the reaction conditions shown intable 27 according to the procedure described in step 1 of Example 15.

TABLE 27 The reaction conditions for preparation of compound H

No.

compound A3: compound (VI) (mol); the amount of compound A3 is 5.47 gReaction solvent Reaction temperature (° C.) Reaction time (h) Productcharacter Quality; yield (%) of product H1

1:1 ethanol 30 12 yellow solid 4.44 g; 71 H2

1:1 ethanol 30 12 yellow solid 4.32 g; 69 H3

1:1 ethanol 30 12 yellow solid 2.63 g; 42 H4

1:1 ethanol 30 12 yellow solid 4.52 g; 74 H5

1:1 ethanol 30 12 yellow solid 2.56 g; 40 H6

1:1 ethanol 30 12 yellow solid 4.89 g; 63 H7

1:1 ethanol 30 12 yellow solid 3.23 g; 50 H8

1:1 ethanol 30 12 yellow solid 3.04 g; 47

TABLE 27-1 The NMR and MS datum of compound H No. ¹H NMR MS H1 ¹H NMR(600 MHz, DMSO-d₆): δ 12.08 (br, 1H), 9.75 (s, 1H), 8.04 (d, 1H), 7.96MS (ESI, (d, 1H), 7.62 (br, 1H), 7.41 (br, 2H), 6.07 (s, 1H), 4.86 (q,1H), 4.15-4.06 (m, 2H), pos. ion) m/z: 3.98-3.86 (m, 3H), 3.58-3.47 (m,2H), 2.85-2.75 (m, 2H), 2.35-2.25 (m, 3H), 2.02 624.6 [M + H]⁺; (br,1H), 1.67-1.62 (m, 2H), 1.25 (d, 3H), 1.09 (t, 3H). H2 ¹H NMR (600 MHz,DMSO-d₆): δ 9.83 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.60 MS (ESI (br,1H), 7.39 (br, 2H), 6.03 (s, 1H), 4.87 (q, 1H), 4.16-4.06 (m, 2H),3.97-3.86 pos. ion) m/z: (m, 3H), 3.59-3.57 (m, 1H), 3.54-3.48 (m, 1H),2.79 (t, 2H), 2.37-2.24 (m, 3H), 2.01 624.6 [M + H]⁺; (t, 1H), 1.68-1.63(m, 2H), 1.22 (d, 3H), 1.12 (t, 3H). H3 ¹H NMR (600 MHz, DMSO-d₆): δ9.79 (s, 1H), 8.02 (d, 1H), 7.96 (d, 1H), 7.58 MS (ESI, (br, 1H), 7.39(br, 2H), 6.05 (s, 1H), 4.86 (q, 1H), 4.17 (d, 1H), 4.13-4.03 (m, 2H),pos. ion) m/z: 3.87 (d, 1H), 3.82 (d, 1H), 3.76-3.72 (m, 1H), 3.62-3.56(m, 1H), 3.37-3.33 (m, 1H), 625.1 [M + H]⁺; 2.94-2.73 (m, 1H), 2.58-2.54(m, 1H), 2.38-2.31 (m, 1H), 2.29-2.21 (m, 1H), 1.89-1.84 (m, 1H),1.68-1.59 (m, 1H), 1.24 (d, 3H), 1.14 (t, 3H). H4 ¹H NMR (600 MHz,DMSO-d₆): δ 9.81 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.59 MS (ESI (br,1H), 7.40 (br, 2H), 6.04 (s, 1H), 4.85 (q, 1H), 4.12-4.03 (m, 3H),3.93-3.86 pos. ion) m/z: (m, 1H), 3.74-3.68 (m, 2H), 3.65-3.61 (m, 1H),2.99 (d, 1H), 2.92 (d, 1H), 2.48-2.44 611.1 [M + H]⁺; (m, 1H), 1.24 (d,3H), 1.21 (d, 3H), 1.12 (t, 3H). H5 ¹H NMR (400 MHz, DMSO-d₆): δ 12.14(s, 1H), 9.87 (s, 1H), 8.04 (d, 1H), 7.96 MS (ESI, (d, 1H), 7.61 (br,1H), 7.38 (br, 2H), 6.09 (s, 1H), 4.87 (q, 1H), 4.16 (d, 1H), pos. ion)m/z: 4.12-4.02 (m, 2H), 3.83 (d, 1H), 3.77-3.74 (m, 1H), 3.60-3.55 (m,1H), 3.50-3.46 639.2 [M + H]⁺; (m, 1H), 2.69 (d, 1H), 2.45-2.41 (m, 1H),2.36-2.31(m, 3H), 2.08-1.88 (m, 1H), 1.79-1.72 (m, 1H), 1.25 (d, 3H),1.20 (d, 3H), 1.14 (t, 3H). H6 ¹H NMR (600 MHz, DMSO-d₆): δ 9.69 (s,1H), 7.98 (d, 1H), 7.94 (d, 1H), 7.59 MS (ESI (br, 1H), 7.40 (br, 2H),6.04 (s, 1H), 4.86-4.81 (m, 1H), 4.31 (d, 1H), 4.10-4.03 pos. ion) m/z:(m, 3H), 3.93-3.90 (m, 1H), 3.52-3.49 (m, 1H), 3.18-3.13 (m, 1H),2.81-2.75 617.1 [M + H]⁺; (m, 1H), 2.48-2.43 (m, 1H), 1.23 (d, 3H), 1.12(t, 3H). H7 ¹H NMR (600 MHz, DMSO-d₆): δ 12.05 (s, 1H), 9.58 (s, 1H),8.04 (d, 1H), 7.96 MS (ESI, (d, 1H), 7.60 (br, 1H), 7.39 (br, 2H), 6.07(s, 1H), 4.86 (q, 1H), 4.15-4.04 (m, 4H), pos. ion) m/z: 3.56-3.51 (m,1H), 3.05-2.94 (m, 2H), 2.63-2.54 (m, 1H), 2.37-2.21 (m, 2H), 645.1 [M +H]⁺; 2.13-2.01 (m, 1H), 1.96-1.89 (m, 1H), 1.58-1.52 (m, 1H), 1.24 (d,3H), 1.12 (t, 3H). H8 ¹H NMR (600 MHz, DMSO-d₆): δ 12.14 (s, 1H), 9.51(s, 1H), 8.01 (d, 1H), 7.95 MS (ESI, (d, 1H), 7.59 (br, 1H), 7.40 (br,2H), 6.09 (s, 1H), 4.87 (q, 1H), 4.16-4.05 (m, 4H), pos. ion) m/z:3.51-3.47 (m, 1H), 3.03-2.92 (m, 2H), 2.61-2.58 (m, 1H), 2.41-2.23 (m,2H), 645.1 [M + H]⁺; 2.14-1.99 (m, 2H), 1.61-1.54 (m, 1H), 1.26 (d, 3H),1.16 (t, 3H).

Step 2)(S)-4-(((R)-6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added anhydrous ethanol (870 g) and lithium (2.43 g,0.35 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then(S)-4-(((R)-6-(2,4-dichlorophenyl)-5-((((R)-1-ethoxy-1-oxopropan-2-yl)oxy)carbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid (59.7 g, 0.1 mol) was added. The reaction mixture was allowed towarm up to 78° C. and stirred for 12 hours. After the reaction, themixture was cooled and concentrated. To the residue was added water(1200 g), the resulting mixture was extracted with ethyl acetate (1200mL) The organic layer was discarded. To the aqueous layer was addedethyl acetate (1280 mL), and the mixture was adjusted to pH 3-6 withconcentrated hydrochloric acid. The organic layer was dried overanhydrous sodium sulfate and concentrated to give the product as ayellow solid (35.7 g, 68%).

MS (ESI, pos.ion) m/z: 524.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 12.86 (br, 1H), 9.84 (s, 1H), 8.03 (d, 1H),7.94 (d, 1H), 7.60 (br, 1H), 7.42-7.36 (m, 2H), 6.05 (s, 1H), 4.25 (d,1H), 4.09-3.91 (m, 4H), 3.83 (dd, 1H), 3.75-3.58 (m, 3H), 3.12-3.03 (m,1H), 2.43-2.36 (m, 1H), 1.06 (t, 3H).

The compound XX can be prepared under the reaction conditions shown intable 28 according to the procedure described in step 2 of Example 15.

TABLE 28 The reaction conditions for preparation of compound XX

No. R³

The mole ratio of Lithium to compound Q; the amount of compound QReaction solvent Reaction temperature (° C.) Reaction time (h) Productcharacter Quality; yield (%) of product XX1 ethyl

5; 6.25 g ethanol 78 2 yellow solid 3.33 g; 60 XX2 ethyl

5; 6.25 g ethanol 78 2 yellow solid 3.21 g; 58 XX3 ethyl

5; 6.25 g ethanol 78 2 yellow solid 2.38 g; 43 XX4 ethyl

5; 6.11 g ethanol 78 12 yellow solid 3.61 g; 67 XX5 ethyl

5; 6.39 g ethanol 78 2 yellow solid 2.38 g; 42 XX6 ethyl

5; 6.17 g ethanol 78 12 yellow solid 2.83 g; 52 XX7 ethyl

5; 6.46 g ethanol 78 2 yellow solid 2.58 g; 45 XX8 ethyl

5; 6.46 g ethanol 78 2 yellow solid 2.87 g; 50 XX9 methyl

5; 5.97 g methanol 64 18 yellow solid 3.53 g; 69 XX10 methyl

5; 6.25 g methanol 64 6 yellow solid 3.13 g; 58 XX11 methyl

5; 6.25 g methanol 64 4 yellow solid 3.02 g; 56 XX12 methyl

5; 6.25 g methanol 64 8 yellow solid 2.21 g; 41 XX13 methyl

5; 6.11 g methanol 64 18 yellow solid 3.36 g; 64 XX14 methyl

5; 6.39 g methanol 64 5 yellow solid 2.21 g; 40 XX15 methyl

5; 6.17 g methanol 64 12 yellow solid 2.6 g; 49 XX16 methyl

5; 6.87 g methanol 64 6 yellow solid 2.57 g; 46 XX17 methyl

5; 6.46 g methanol 64 6 yellow solid 2.63 g; 47

TABLE 28-1 The NMR and MS datum of compound XX No. ¹H NMR MS XX1 ¹H NMR(400 MHz, DMSO-d₆): δ 12.04 (s, 1H), 9.66 (s, 1H), 8.02 (d, 1H), MS(ESI, pos. ion) 7.95 (d, 1H), 7.61 (br, 1H), 7.38 (br, 2H), 6.05 (s,1H), 3.96 (q, 2H), m/z: 553.2 [M + H]⁺; 3.89-3.86 (m, 3H), 3.61-3.46 (m,2H), 2.77 (t, 2H), 2.36-2.23 (m, 3H), 2.02 (t, 1H), 1.63 (dd, 2H), 1.05(t, 3H). XX2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.66 (s, 1H),8.03 (d, 1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.61 (br, 1H), 7.40 (br,2H), 6.06 (s, 1H), 3.98-3.93 (m, H), m/z: 552.9 [M + H]⁺; 3.86-3.82 (m,2H), 3.58-3.48 (m, 2H), 2.87 (d, 1H), 2.63 (d, 1H), 2.36-2.23 (m, 3H),2.10 (t, 1H), 1.72-1.63 (m, 2H), 1.06 (t, 3H). XX3 ¹H NMR (400 MHz,DMSO-d₆): δ 9.84 (s, 1H), 8.03 (d, 1H), 7.95 (d, 1H), MS (ESI, pos. ion)7.60 (br, 1H), 7.40 (br, 2H), 6.05 (s, 1H), 4.18 (d, 1H), 3.97 (q, 2H),3.90 m/z: 552.9 [M + H]⁺; (d, 1H), 3.82-3.80 (m, 1H), 3.74-3.72 (m, 1H),3.61-3.55 (m, 1H), 3.37-3.35 (m, 1H), 2.78-2.76 (m, 1H), 2.56-2.54 (m,1H), 2.49-2.46 (m, 1H), 2.35-2.20 (m, 2H), 1.88-1.83 (m, 1H), 1.64-1.54(m, 1H), 1.07 (t, 3H). XX4 ¹H NMR (400 MHz, DMSO-d₆): δ 13.12 (s, 1H),9.79 (s, 1H), 8.02 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.60 (br,1H), 7.39 (br, 2H), 6.03 (s, 1H), 4.06 (d, 1H), 3.96 m/z: 539.2 [M +H]⁺; (q, 2H), 3.90-3.87 (m, 1H), 3.74-3.59 (m, 3H), 3.47-3.43 (m, 1H),2.98 (d, 1H), 2.90 (d, 1H), 1.20 (d, 3H), 1.04 (t, 3H). XX5 ¹H NMR (400MHz, DMSO-d₆): δ 12.09 (s, 1H), 9.76 (s, 1H), 8.03 (d, 1H), MS (ESI,pos. ion) 7.96 (d, 1H), 7.59 (br, 1H), 7.38 (br, 2H), 6.06 (s, 1H), 4.15(d, 1H), m/z: 567.1 [M + H]⁺; 4.02-3.93 (m, 2H), 3.87 (d, 1H), 3.78-3.73(m, 1H), 3.60-3.54 (m, 1H), 3.51-3.46 (m, 1H), 2.67 (d, 1H), 2.45-2.41(m, 1H), 2.38-2.30 (m, 3H), 2.04-1.92 (m, 1H), 1.81-1.73 (m, 1H), 1.21(d, 3H), 1.08 (t, 3H). XX6 ¹H NMR (600 MHz, DMSO-d₆): δ 12.90 (s, 1H),9.67 (s, 1H), 7.98 (d, 1H), MS (ESI, pos. ion) 7.92 (d, 1H), 7.60 (br,1H), 7.42 (br, 2H), 6.03 (s, 1H), 4.33 (d, 1H), 4.08 m/z: 545.1 [M +H]⁺; (d, 1H), 3.96 (q, 2H), 3.92-3.89 (m, 1H), 3.53-3.48 (m, 1H),3.19-3.13 (m, 1H), 2.79-2.73 (m, 1H), 2.47-2.45 (m, 1H), 1.06 (t, 3H).XX7 ¹H NMR (400 MHz, DMSO-d₆): δ 12.05 (s, 1H), 9.52 (s, 1H), 8.00 (d,1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.60 (br, 1H), 7.41 (br, 2H), 6.04(s, 1H), 4.14 (dd, 2H), 3.97 m/z: 573.3 [M + H]⁺; (q, 2H), 3.57-3.49 (m,1H), 3.07-2.97 (m, 2H), 2.58-2.54 (m, 1H), 2.34-2.21 (m, 2H), 2.18-2.03(m, 1H), 1.95-1.91 (m, 1H), 1.60-1.49 (m, 1H), 1.06 (t, 3H). XX8 ¹H NMR(400 MHz, DMSO-d₆): δ 12.17 (s, 1H), 9.47 (s, 1H), 8.00 (d, 1H), MS(ESI, pos. ion) 7.94 (d, 1H), 7.60 (br, 1H), 7.45-7.37 (m, 2H), 6.06 (s,1H), 4.15 (dd, 2H), m/z: 573.2 [M + H]⁺; 3.96 (q, 2H), 3.47-3.39 (m,1H), 3.01-2.86 (m, 2H), 2.59-2.53 (m, 1H), 2.38-2.25 (m, 2H), 2.15-2.01(m, 2H), 1.65-1.55 (m, 1H), 1.05 (t, 3H). XX9 ¹H NMR (400 MHz, CDCl₃): δ8.42 (s, 1H), 7.87 (d, 1H), 7.50 (d, 1H), MS (ESI, pos. ion) 7.42 (d,1H), 7.28 (br, 1H), 7.20 (dd, 1H), 6.20 (s, 1H), 4.23-4.15 (m, 2H), m/z:511.1 [M + H]⁺; 4.13-4.05 (m, 2H), 3.90-3.80 (m, 2H), 3.61 (s, 3H),3.59-3.57 (m, 1H), 3.27-3.23 (m, 1H), 2.62-2.54 (m, 1H). XX10 ¹H NMR(400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 9.70 (s, 1H), 8.01 (d, 1H), MS(ESI, pos. ion) 7.94 (d, 1H), 7.59 (br, 1H), 7.37 (br, 2H), 6.04 (s,1H), 3.89-3.86 (m, 3H), m/z: 538.8 [M + H]⁺; 3.63-3.57 (m, 1H), 3.52 (s,3H), 3.49-3.47 (m, 1H), 2.76 (t, 2H), 2.39-2.24 (m, 3H), 2.04 (t, 1H),1.63 (dd, 2H). XX11 ¹H NMR (600 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.70 (s,1H), 8.03 (d, 1H), MS (ESI, pos. ion) 7.94 (d, 1H), 7.59 (br, 1H), 7.40(br, 2H), 6.03 (s, 1H), 3.96 (d, 1H), m/z: 539.1 [M + H]⁺; 3.85-3.80 (m,2H), 3.57-3.55 (m, 1H), 3.52 (s, 3H), 3.51-3.48 (m, 1H), 2.88 (d, 1H),2.61 (d, 1H), 2.38-2.21 (m, 3H), 2.16-2.09 (m, 1H), 1.72-1.65 (m, 2H).XX12 ¹H NMR (400 MHz, DMSO-d₆): δ 12.17 (s, 1H), 9.89 (s, 1H), 8.04 (d,1H), MS (ESI, pos. ion) 7.95 (d, 1H), 7.60 (br, 1H), 7.42-7.37 (m, 2H),6.04 (s, 1H), 4.18 (d, 1H), m/z: 538.9 [M + H]⁺; 3.90 (d, 1H), 3.84-3.80(m, 1H), 3.76-3.72 (m, 1H), 3.61-3.56 (m, 1H), 3.53 (s, 3H), 3.46-3.42(m, 1H), 3.30-3.26 (m, 1H), 2.80-2.75 (m, 1H), 2.56-2.53 (m, 1H),2.37-2.22 (m, 2H), 1.93-1.83 (m, 1H), 1.62-1.58 (m, 1H). XX13 ¹H NMR(600 MHz, DMSO-d₆): δ 13.00 (s, 1H), 9.83 (s, 1H), 8.03 (d, 1H), MS(ESI, pos. ion) 7.94 (d, 1H), 7.60 (br, 1H), 7.39-7.36 (m, 2H), 6.02 (s,1H), 4.05 (d, 1H), m/z: 524.7 [M + H]⁺; 3.90-3.86 (m, 1H), 3.74 (d, 1H),3.70-3.68 (m, 1H), 3.65-3.60 (m, 1H), 3.51 (s, 3H), 3.42-3.36 (m, 1H),2.99 (d, 1H), 2.89 (d, 1H), 1.20 (d, 3H). XX14 ¹H NMR (400 MHz,DMSO-d₆): δ 12.09 (s, 1H), 9.76 (s, 1H), 8.03 (d, 1H), MS (ESI, pos.ion) 7.94 (d, 1H), 7.59 (br, 1H), 7.39 (br, 1H), 6.03 (s, 1H), 4.17 (d,1H), 3.89 m/z: 553.1 [M + H]⁺; (d, 1H), 3.78-3.74 (m, 1H), 3.61-3.55 (m,1H), 3.53 (s, 3H), 3.50-3.46 (m, 1H), 2.67 (d, 1H), 2.48-2.42 (m, 1H),2.37-2.31 (m, 3H), 2.03-1.93 (m, 1H), 1.82-1.73 (m, 1H), 1.21 (d, 3H).XX15 ¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.88 (d, 1H), 7.57 (d,1H), MS (ESI, pos. ion) 7.45 (br, 1H), 7.28 (br, 2H), 6.15 (s, 1H), 4.67(d, 1H), 3.98-3.93 (m, 1H), m/z: 531.1 [M + H]⁺; 3.76 (d, 1H), 3.64 (s,3H), 3.60-3.55 (m, 1H), 3.34-3.24 (m, 1H), 2.86-2.76 (m, 1H), 2.68-2.54(m, 1H). XX16 ¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (br, 1H), 9.56 (s, 1H),7.99 MS (ESI, pos. ion) (d, 1H), 7.92 (d, 1H), 7.60 (br, 1H), 7.39 (br,2H), 6.02 (s, 1H), 4.14 (dd, 2H), m/z: 559.0 [M + H]⁺; 3.52 (s, 3H),3.08-2.94 (m, 3H), 2.55-2.53 (m, 1H), 2.30-2.19 (m, 2H), 2.12-1.99 (m,1H), 1.95-1.84 (m, 1H), 1.60-1.46 (m, 1H). XX17 ¹H NMR (400 MHz,DMSO-d₆): δ 12.15 (s, 1H), 9.52 (s, 1H), 8.00 (d, 1H), MS (ESI, pos.ion) 7.94 (d, 1H), 7.60 (s, 1H), 7.41 (br, 2H), 6.05 (s, 1H), 4.13 (dd,2H), 3.52 m/z: 558.6 [M + H]⁺; (s, 3H), 3.47-3.39 (m, 1H), 3.01-2.87 (m,2H), 2.59-2.53 (m, 1H), 2.37-2.25 (m, 2H), 2.15-2.02 (m, 2H), 1.64-1.55(m, 1H).

Example 16: The Preparation of (R)-ethyl4-(2,4-dichlorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

Step 1) (R)-ethyl4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added anhydrous ethanol (374 g) and lithium (2.43 g,0.35 mol) in turn. The mixture was stirred at 43° C. until the lithiumwas consumed entirely, and then (R)-(R)-1-ethoxy-1-oxopropan-2-yl4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(46.8 g, 0.1 mol) was added. The reaction mixture was stirred at 78° C.for 6 hours. After the reaction, the reaction mixture was cooled to 10°C., kept at 10° C. and stirred for 8 hours. The mixture was filtered.The filter cake was washed with anhydrous ethanol (47 g) and water (500g) in turn, and then dried in vacuo at 60° C. for 8 hours to obtain theproduct as a yellow solid (28.1 g, 71%).

[a]_(D) ²⁵=−39.07 (c=0.3032 g/100 mL, MeOH);

MS (ESI, pos.ion) m/z: 396.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 9.93 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H),7.58 (d, 1H), 7.41 (dd, 1H), 7.35 (d, 1H), 6.00 (s, 1H), 3.93 (q, 2H),2.46 (s, 3H), 1.03 (t, 3H).

The compound TT can be prepared under the reaction conditions shown intable 29 according to the procedure described in step 1 of Example 16.

TABLE 29 The reaction conditions for preparation of compound TT

The mole ratio of Lithium to The mass compound ratio of (10); thereaction amount of solvent to Reaction Quality; compound Reactioncompound temperature Reaction Product yield (%) No. R³ (10) is 46.8 gsolvent (10) (° C.) time (h) character of product TT1 ethyl 2.5 ethanol10 78 12 yellow 17 g; solid 43 TT1 ethyl 3 ethanol 6 78 8 yellow 28.5 g;solid 72 TT1 ethyl 4 ethanol 10 78 4 yellow 21.4 g; solid 54 TT1 ethyl 5ethanol 20 78 24 yellow 18.6 g; solid 47 TT1 ethyl 6 ethanol 30 78 12yellow 15.4 g; solid 39 TT1 ethyl 8 ethanol 20 78 12 yellow 17.9 g;solid 45 TT2 methyl 3 methanol 3 64 20 yellow 22.9 g: solid 60% TT2methyl 3 methanol 4 64 6 yellow 17.6 g; solid 46 TT2 methyl 4 methanol 664 8 yellow 12.9 g; solid 34

TABLE 29-1 The NMR, MS and specific rotation datum of the compound TTNo. ¹H NMR MS specific rotation TT1 ¹H NMR (400 MHz, DMSO-d₆): δ 9.93(s, 1H), 7.97 MS (ESI, [α]_(D) ²⁵ = −39.07 (c = (d, 1H), 7.90 (d, 1H),7.58 (d, 1H), 7.41 (dd, 1H), 7.35 pos. ion) m/z: 0.3032 g/100 (d, 1H),6.00 (s, 1H), 3.93 (q, 2H), 2.46 (s, 3H), 1.03 (t, 3H). 396.1 [M + H]⁺;mL, MeOH); TT2 ¹H NMR (400 MHz, DMSO-d₆): δ 9.99 (s, 1H), 7.98 MS (ESI,[α]_(D) ²⁵ = −46.08 (c = (d, 1H), 7.90 (d, 1H), 7.59 (d, 1H), 7.40 (dd,1H), 7.33 pos. ion) m/z: 0.3038 g/100 (d, 1H), 5.98 (s, 1H), 3.49 (s,3H), 2.47 (s, 3H). 382.1 [M + H]⁺ mL, MeOH);

Step 2) (R)-ethyl4-(2,4-dichlorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl4-(2,4-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(39.6 g, 0.1 mol) and CCl₄ (800 mL), followed by NBS (19.6 g, 0.11 mol)at 70° C. The mixture was stirred for 30 min After the reaction, themixture was cooled and filtered. The filtrate was concentrated to obtainthe product as a yellow solid (37.1 g, 78%).

MS (ESI, pos.ion) m/z: 475.6 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 8.03 (d, 1H), 7.98 (d, 1H), 7.66-7.62 (m,1H), 7.47-7.35 (m, 2H), 5.99 (s, 1H), 4.82 (br, 2H), 4.02 (q, 2H), 1.09(t, 3H).

The compound WW can be prepared under the reaction conditions shown intable 30 according to the procedure described in step 2 of Example 16.

TABLE 30 The reaction conditions for preparation of compound WW

The mole The ratio of mass NBS to ratio of Qual- compound reaction Reac-ity; TT; the Reac- solvent tion yield amount of tion to com- temper-Product (%) of compound sol- pound ature charac- pro- No. R³ TT vent(TT) (° C.) ter duct WW1 ethyl 1.0; DCM 10 39 yellow 35.2 g; 39.6 gsolid 72 WW1 ethyl 1.0; CHCl₃ 20 61 yellow 36.3 g; 39.6 g solid 75 WW1ethyl 1.1; CCl₄ 30 76 yellow 44.3 g; 39.6 g solid 80 WW2 methyl 1.0; DCM10 39 yellow 29.9 g; 38.2 g solid 70 WW2 methyl 1.1; CHCl₃ 20 61 yellow30.8 g; 38.2 g solid 72 WW2 methyl 1.1; CCl₄ 30 76 yellow 34.9 g; 38.2 gsolid 79

TABLE 30-1 The NMR and MS datum of compound WW No. ¹H NMR MS WW1 ¹H NMR(600 MHz, DMSO-d₆): δ 8.03 (d, 1H), 7.98 (d, 1H), 7.66-7.62 MS (ESI,pos. ion) (m, 1H), 7.47-7.35 (m, 2H), 5.99 (s, 1H), 4.82 (br, 2H), 4.02(q, 2H), 1.09 m/z: 475.6 (t, 3H). [M + H]⁺; WW2 ¹H NMR (600 MHz,DMSO-d₆): δ 9.91 (s, 1H), 8.01 (d, 1H), 7.96 (d, 1H), MS (ESI, pos. ion)7.62 (br, 1H), 7.40 (br, 2H), 6.01 (s, 1H), 4.86 (br, 2H), 3.56 (s, 3H).m/z: 459.9 [M + H]⁺;

Step 3) (R)-ethyl4-(2,4-dichlorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

To a flask were added (R)-ethyl4-(2,4-dichlorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(47.5 g, 0.1 mol), anhydrous ethanol (285 g) and morpholine (34.8 g, 0.4mol). The mixture was stirred at 25° C. for 6 hours. After the reaction,the mixture was concentrated. To the residue was added ethyl acetate(475 g), the resulting mixture was washed with water (250 mL×2). Theorganic layer was concentrated to give the product as tawny oil (37.5 g,78%)

MS (ESI, pos.ion) m/z: 480.7 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H),7.60 (s, 1H), 7.39 (s, 2H), 6.06 (s, 1H), 3.97 (q, 2H), 3.92 (dd, 2H),3.67 (br, 4H), 2.56 (br, 4H), 1.06 (t, 3H).

The compound UU can be prepared under the reaction conditions shown intable 31 according to the procedure described in step 3 of Example 16.

TABLE 31 The reaction conditions for preparation of compound UU

The mole ratio of compound The mass (6) to ratio of compound reactionWW; the solvent amount of to com- Reaction Quality; compound Reactionpound temperature Reaction Product yield (%) No. R³ WW solvent (WW) (°C.) time (h) character of product UU1 ethyl 2; ethanol 20 25 2 tawny36.6 g; 47.5 g oil 76 UU1 ethyl 3; acetone 10 40 10 tawny 35.1 g; 47.5 goil 73 UU1 ethyl 4; methanol 10 30 6 tawny 34.6 g; 47.5 g oil 72 UU1ethyl 5; ethyl 20 50 24 tawny 34.2 g; 47.5 g acetate oil 71 UU1 ethyl 6;DCM 8 39 6 tawny 31.7 g; 47.5 g oil 66 UU1 ethyl 3; DMF 4 60 1 tawny33.2 g; 47.5 g oil 69 UU1 ethyl 4; THF 6 50 8 tawny 34.6 g; 47.5 g oil72 UU2 methyl 2; ethanol 20 25 2 tawny 33.2 g; 46.1 g oil 71 UU2 methyl3; acetone 10 40 10 tawny 36.9 g; 46.1 g oil 79 UU2 methyl 4; methanol10 30 6 tawny 36 g; 46.1 g oil 77 UU2 methyl 5; ethyl 20 50 24 tawny34.1 g; 46.1 g acetate oil 73 UU2 methyl 6; DCM 8 39 6 tawny 31.3 g;46.1 g oil 67 UU2 methyl 3; DMF 4 60 1 tawny 33.2 g; 46.1 g oil 71 UU2methyl 4; THF 6 50 8 tawny 31.8 g; 46.1 g oil 68

TABLE 31-1 The NMR and MS datum of compound UU No. ¹H NMR MS UU1 ¹H NMR(600 MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.60 MS(ESI, pos. ion) (s, 1H), 7.39 (s, 2H), 6.06 (s, 1H), 3.97 (q, 2H), 3.92(dd, 2H), 3.67 (br, 4H), 2.56 m/z: 480.7 (br, 4H), 1.06 (t, 3H). [M +H]⁺; UU2 ¹H NMR (400 MHz, CDCl₃): δ 9.73 (s, 1H), 7.87 (d, 1H), 7.47 (d,1H), 7.42 MS (ESI, pos. ion) (d, 1H), 7.24 (d, 1H), 7.18 (dd, 1H), 6.21(s, 1H), 4.02 (d, 1H), 3.89 (d, 1H), 3.85 m/z: 467.1 (t, 4H), 3.62 (s,3H), 2.65 (t, 4H). [M + H]⁺;

Example 17: The Preparation of(S)-4-(((R)-6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylicacid

To a flask were added (R)-ethyl4-(2,4-dichlorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(4.75 g, 10 mmol), (S)-morpholine-3-carboxylic acid (1.31 g, 10 mmol),potassium carbonate (2.76 g, 20 mmol) and ethanol (95 mL). The mixturewas stirred at 30° C. for 12 hours. After the reaction, the mixture wasfiltered. The filtrate was concentrated. To the residue was added water(100 mL), the resulting mixture was extracted with ethyl acetate (100mL). The organic layer was discarded. To the aqueous layer was addedethyl acetate (100 mL), the mixture was adjusted to pH 3-6 withconcentrated hydrochloric acid. The organic layer was dried overanhydrous sodium sulfate and concentrated to give the product as ayellow solid (4.1 g, 78%).

MS (ESI, pos.ion) m/z: 524.7 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ 12.86 (br, 1H), 9.84 (s, 1H), 8.03 (d, 1H),7.94 (d, 1H), 7.60 (br, 1H), 7.42-7.36 (m, 2H), 6.05 (s, 1H), 4.25 (d,1H), 4.09-3.91 (m, 4H), 3.83 (dd, 1H), 3.75-3.58 (m, 3H), 3.12-3.03 (m,1H), 2.43-2.36 (m, 1H), 1.06 (t, 3H).

The compound XX can be prepared under the reaction conditions shown intable 32 according to the procedure described in Example 17.

TABLE 32 The reaction conditions for preparation of compound XX

No. R³

The mole ratio of compound WW to compound (VI); the amount of compoundWW Reaction solvent The mass ratio of reaction solvent to com- pound WWReaction temperature (° C.) Reaction time (h) Product character Quality;yield (%) of product XX1 ethyl

1; 4.75 g ethanol 8 30 4 yellow solid 3.76 g; 68 XX2 ethyl

1; 4.75 g ethanol 4 30 8 yellow solid 3.65 g; 66 XX3 ethyl

1; 4.75 g ethanol 20 30 24 yellow solid 2.38 g; 43 XX4 ethyl

1; 4.75 g ethanol 30 30 6 yellow solid 4.2 g; 78 XX5 ethyl

1; 4.75 g ethanol 15 30 24 yellow solid 3.12 g; 55 XX6 ethyl

1; 4.75 g ethanol 20 30 6 yellow solid 3.98 g; 73 XX7 ethyl

1; 4.75 g ethanol 25 30 12 yellow solid 3.55 g; 62 XX8 ethyl

1; 4.75 g ethanol 14 30 12 yellow solid 3.67 g; 64 XX9 methyl

1; 4.61 g ethanol 8 30 4 yellow solid 3.73 g; 73 XX10 methyl

1; 4.61 g ethanol 4 30 8 yellow solid 3.4 g; 63 XX11 methyl

1; 4.61 g ethanol 10 30 12 yellow solid 3.34 g; 62 XX12 methyl

1; 4.61 g ethanol 30 30 6 yellow solid 2.2 g; 41 XX13 methyl

1; 4.61 g ethanol 8 30 12 yellow solid 3.83 g; 73 XX14 methyl

1; 4.61 g ethanol 20 30 6 yellow solid 2.49 g; 45 XX15 methyl

1; 4.61 g ethanol 25 30 12 yellow solid 3.77 g; 71 XX16 methyl

1; 4.61 g ethanol 14 30 12 yellow solid 3.3 g; 59 XX17 methyl

1; 4.61 g ethanol 15 30 24 yellow solid 3.63 g; 65

TABLE 32-1 The NMR and MS datum of compound XX No. ¹H NMR MS XX1 ¹H NMR(400 MHz, DMSO-d₆): δ 12.04 (s, 1H), 9.66 (s, 1H), 8.02 MS (ESI, pos.ion) (d, 1H), 7.95 (d, 1H), 7.61 (br, 1H), 7.38 (br, 2H), 6.05 (s, 1H),3.96 m/z: 553.2 (q, 2H), 3.89-3.86 (m, 3H), 3.61-3.46 (m, 2H), 2.77 (t,2H), 2.36-2.23 [M + H]⁺; (m, 3H), 2.02 (t, 1H), 1.63 (dd, 2H), 1.05 (t,3H). XX2 ¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 9.66 (s, 1H), 8.03MS (ESI, pos. ion) (d, 1H), 7.95 (d, 1H), 7.61 (br, 1H), 7.40 (br, 2H),6.06 (s, 1H), 3.98-3.93 m/z: 552.9 (m, 3H), 3.86-3.82 (m, 2H), 3.58-3.48(m, 2H), 2.87 (d, 1H), 2.63 (d, 1H), [M + H]⁺; 2.36-2.23 (m, 3H), 2.10(t, 1H), 1.72-1.63 (m, 2H), 1.06 (t, 3H). XX3 ¹H NMR (400 MHz, DMSO-d₆):δ 9.84 (s, 1H), 8.03 (d, 1H), 7.95 MS (ESI, pos. ion) (d, 1H), 7.60 (br,1H), 7.40 (br, 2H), 6.05 (s, 1H), 4.18 (d, 1H), 3.97 m/z: 552.9 (q, 2H),3.90 (d, 1H), 3.82-3.80 (m, 1H), 3.74-3.72 (m, 1H), 3.61-3.55 [M + H]⁺;(m, 1H), 3.37-3.35 (m, 1H), 2.78-2.76 (m, 1H), 2.56-2.54 (m, 1H),2.49-2.46 (m, 1H), 2.35-2.20 (m, 2H), 1.88-1.83 (m, 1H), 1.64-1.54 (m,1H), 1.07 (t, 3H). XX4 ¹H NMR (400 MHz, DMSO-d₆): δ 13.12 (s, 1H), 9.79(s, 1H), 8.02 MS (ESI, pos. ion) (d, 1H), 7.94 (d, 1H), 7.60 (br, 1H),7.39 (br, 2H), 6.03 (s, 1H), 4.06 m/z: 539.2 (d, 1H), 3.96 (q, 2H),3.90-3.87 (m, 1H), 3.74-3.59 (m, 3H), 3.47-3.43 [M + H]⁺; (m, 1H), 2.98(d, 1H), 2.90 (d, 1H), 1.20 (d, 3H), 1.04 (t, 3H). XX5 ¹H NMR (400 MHz,DMSO-d₆): δ 12.09 (s, 1H), 9.76 (s, 1H), 8.03 MS (ESI, pos. ion) (d,1H), 7.96 (d, 1H), 7.59 (br, 1H), 7.38 (br, 2H), 6.06 (s, 1H), 4.15 m/z:567.1 (d, 1H), 4.02-3.93 (m, 2H), 3.87 (d, 1H), 3.78-3.73 (m, 1H),3.60-3.54 [M + H]⁺; (m, 1H), 3.51-3.46 (m, 1H), 2.67 (d, 1H), 2.45-2.41(m, 1H), 2.38-2.30 (m, 3H), 2.04 -1.92 (m, 1H), 1.81-1.73 (m, 1H), 1.21(d, 3H), 1.08 (t, 3H). XX6 ¹H NMR (600 MHz, DMSO-d₆): δ 12.90 (s, 1H),9.67 (s, 1H), 7.98 MS (ESI, pos. ion) (d, 1H), 7.92 (d, 1H), 7.60 (br,1H), 7.42 (br, 2H), 6.03 (s, 1H), 4.33 m/z: 545.1 (d, 1H), 4.08 (d, 1H),3.96 (q, 2H), 3.92-3.89 (m, 1H), 3.53-3.48 (m, 1H), [M + H]⁺; 3.19-3.13(m, 1H), 2.79-2.73 (m, 1H), 2.47-2.45 (m, 1H), 1.06 (t, 3H). XX7 ¹H NMR(400 MHz, DMSO-d₆): δ 12.05 (s, 1H), 9.52 (s, 1H), 8.00 MS (ESI, pos.ion) (d, 1H), 7.94 (d, 1H), 7.60 (br, 1H), 7.41 (br, 2H), 6.04 (s, 1H),4.14 m/z: 573.3 (dd, 2H), 3.97 (q, 2H), 3.57-3.49 (m, 1H), 3.07-2.97 (m,2H), 2.58-2.54 [M + H]⁺; (m, 1H), 2.34-2.21 (m, 2H), 2.18-2.03 (m, 1H),1.95-1.91 (m, 1H), 1.60-1.49 (m, 1H), 1.06 (t, 3H). XX8 ¹H NMR (400 MHz,DMSO-d₆): δ 12.17 (s, 1H), 9.47 (s, 1H), 8.00 (d, 1H), 7.94 (d, 1H),7.60 (br, 1H), 7.45-7.37 (m, 2H), 6.06 (s, 1H), 4.15 MS (ESI, pos. ion)(dd, 2H), 3.96 (q, 2H), 3.47-3.39 (m, 1H), 3.01-2.86 (m, 2H), 2.59-2.53m/z: 573.2 (m, 1H), 2.38-2.25 (m, 2H), 2.15-2.01 (m, 2H), 1.65-1.55 (m,1H), 1.05 [M + H]⁺; (t, 3H). XX9 ¹H NMR (400 MHz, CDCl₃): δ 8.42 (s,1H), 7.87 (d, 1H), 7.50 (d, 1H), MS (ESI, pos. ion) 7.42 (d, 1H), 7.28(br, 1H), 7.20 (dd, 1H), 6.20 (s, 1H), 4.23-4.15 (m, 2H), m/z: 511.14.13-4.05 (m, 2H), 3.90-3.80 (m, 2H), 3.61 (s, 3H), 3.59-3.57 (m, 1H),[M + H]⁺; 3.27-3.23 (m, 1H), 2.62-2.54 (m, 1H). XX10 ¹H NMR (400 MHz,DMSO-d₆): δ 12.03 (s, 1H), 9.70 (s, 1H), 8.01 MS (ESI, pos. ion) (d,1H), 7.94 (d, 1H), 7.59 (br, 1H), 7.37 (br, 2H), 6.04 (s, 1H), 3.89-3.86m/z: 538.8 (m, 3H), 3.63-3.57 (m, 1H), 3.52 (s, 3H), 3.49-3.47 (m, 1H),2.76 (t, 2H), [M + H]⁺; 2.39-2.24 (m, 3H), 2.04 (t, 1H), 1.63 (dd, 2H).XX11 ¹H NMR (600 MHz, DMSO-d₆): δ 12.06 (s, 1H), 9.70 (s, 1H), 8.03 MS(ESI, pos. ion) (d, 1H), 7.94 (d, 1H), 7.59 (br, 1H), 7.40 (br, 2H),6.03 (s, 1H), 3.96 m/z: 539.1 (d, 1H), 3.85-3.80 (m, 2H), 3.57-3.55 (m,1H), 3.52 (s, 3H), 3.51-3.48 [M + H]⁺; (m, 1H), 2.88 (d, 1H), 2.61 (d,1H), 2.38-2.21 (m, 3H), 2.16-2.09 (m, 1H), 1.72-1.65 (m, 2H). XX12 ¹HNMR (400 MHz, DMSO-d₆): δ 12.17 (s, 1H), 9.89 (s, 1H), 8.04 MS (ESI,pos. ion) (d, 1H), 7.95 (d, 1H), 7.60 (br, 1H), 7.42-7.37 (m, 2H), 6.04(s, 1H), 4.18 m/z: 538.9 (d, 1H), 3.90 (d, 1H), 3.84-3.80 (m, 1H),3.76-3.72 (m, 1H), 3.61-3.56 [M + H]⁺; (m, 1H), 3.53 (s, 3H), 3.46-3.42(m, 1H), 3.30-3.26 (m, 1H), 2.80-2.75 (m, 1H), 2.56-2.53 (m, 1H),2.37-2.22 (m, 2H), 1.93-1.83 (m, 1H), 1.62-1.58 (m, 1H). XX13 ¹H NMR(600 MHz, DMSO-d₆): δ 13.00 (s, 1H), 9.83 (s, 1H), 8.03 MS (ESI, pos.ion) (d, 1H), 7.94 (d, 1H), 7.60 (br, 1H), 7.39-7.36 (m, 2H), 6.02 (s,1H), 4.05 m/z: 524.7 (d, 1H), 3.90-3.86 (m, 1H), 3.74 (d, 1H), 3.70-3.68(m, 1H), 3.65-3.60 [M + H]⁺; (m, 1H), 3.51 (s, 3H), 3.42-3.36 (m, 1H),2.99 (d, 1H), 2.89 (d, 1H), 1.20 (d, 3H). XX14 ¹H NMR (400 MHz,DMSO-d₆): δ 12.09 (s, 1H), 9.76 (s, 1H), 8.03 MS (ESI, pos. ion) (d,1H), 7.94 (d, 1H), 7.59 (br, 1H), 7.39 (br, 1H), 6.03 (s, 1H), 4.17 m/z:553.1 (d, 1H), 3.89 (d, 1H), 3.78-3.74 (m, 1H), 3.61-3.55 (m, 1H), 3.53(s, 3H), [M + H]⁺; 3.50-3.46 (m, 1H), 2.67 (d, 1H), 2.48-2.42 (m, 1H),2.37-2.31 (m, 3H), 2.03 -1.93 (m, 1H), 1.82-1.73 (m, 1H), 1.21 (d, 3H).XX15 ¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.88 (d, 1H), 7.57 (d,1H), MS (ESI, pos. ion) 7.45 (br, 1H), 7.28 (br, 2H), 6.15 (s, 1H), 4.67(d, 1H), 3.98-3.93 (m, 1H), m/z: 531.1 3.76 (d, 1H), 3.64 (s, 3H),3.60-3.55 (m, 1H), 3.34-3.24 (m, 1H), [M + H]⁺; 2.86-2.76 (m, 1H),2.68-2.54 (m, 1H). XX16 ¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (br, 1H),9.56 (s, 1H), 7.99 MS (ESI, pos. ion) (d, 1H), 7.92 (d, 1H), 7.60 (br,1H), 7.39 (br, 2H), 6.02 (s, 1H), 4.14 m/z: 559.0 (dd, 2H), 3.52 (s,3H), 3.08-2.94 (m, 3H), 2.55-2.53 (m, 1H), 2.30-2.19 [M + H]⁺; (m, 2H),2.12-1.99 (m, 1H), 1.95-1.84 (m, 1H), 1.60-1.46 (m, 1H). XX17 ¹H NMR(400 MHz, DMSO-d₆): δ 12.15 (s, 1H), 9.52 (s, 1H), 8.00 (d, 1H), 7.94(d, 1H), 7.60 (s, 1H), 7.41 (br, 2H), 6.05 (s, 1H), 4.13 MS (ESI, pos.ion) (dd, 2H), 3.52 (s, 3H), 3.47-3.39 (m, 1H), 3.01-2.87 (m, 2H),2.59-2.53 m/z: 558.6 (m, 1H), 2.37-2.25 (m, 2H), 2.15-2.02 (m, 2H),1.64-1.55 (m, 1H). [M + H]⁺;

In the specification, Unless specified or limited otherwise, terms suchas “first” and “second” are used herein for purposes of description andare not intended to indicate or imply relative importance orsignificance.

Reference throughout this specification to “an embodiment,” “someembodiments,” “one embodiment”, “another example,” “an example,” “aspecific examples,” or “some examples,” means that a particular feature,structure, material, or characteristic described in connection with theembodiment or example is included in at least one embodiment or exampleof the present disclosure. Thus, the appearances of the phrases such as“in some embodiments,” “in one embodiment”, “in an embodiment”, “inanother example”, “in an example,” “in a specific examples,” or “in someexamples,” in various places throughout this specification are notnecessarily referring to the same embodiment or example of the presentdisclosure. Furthermore, the particular features, structures, materials,or characteristics may be combined in any suitable manner in one or moreembodiments or examples.

Although explanatory embodiments have been shown and described, it wouldbe appreciated by those skilled in the art that the above embodimentscannot be construed to limit the present disclosure, and changes,alternatives, and modifications can be made in the embodiments withoutdeparting from spirit, principles and scope of the present disclosure.

What is claimed is:
 1. A process for preparing a dihydropyrimidinecompound having Formula (I), or a tautomer thereof having Formula (Ia),

wherein each R¹ and R² is independently F, Cl, or Br; R³ is C₁₋₄ alkyl;Z is —O—, —S—, —S(═O)_(t), or —N(R⁴)—; Y is —O—, —S—, —S(═O)_(t),—(CH₂)_(q)—, or —N(R⁵)—; each t and q is independently 0, 1, or 2; eachof R⁴ and R⁵ is independently H or C₁₋₄ alkyl; each R⁶ is independentlyH, deuterium, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄ alkylamino,C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH,—S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂,—(CR⁷R^(7a))_(t)—N(R^(8a))₂, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)); eachR^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together withthe carbon atom to which they are attached, form a C₃₋₆ cycloalkylgroup, C₂₋₉ heterocyclyl group, or —(C═O)—; each R⁸ and R^(8a) isindependently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl, C₁₋₄ alkoxy, C₁₋₆alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆ cycloalkyl, C₂₋₉heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉heterocyclyl-S(═O)_(q)—, C₁₋₉ heteroaryl-S(═O)_(q)—, C₃₋₆cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH,—(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; each R⁹is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkylthio,C₃₋₆ cycloalkyl, —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or—(CR^(7a))_(m)—C(═O)O—R⁸; R¹⁰ is H or deuterium; n is 0, 1, 2, 3, 4, or5; each m is independently 0, 1, 2, 3, or 4; f is 1, 2, 3, or 4; and jis 0, 1, or 2; wherein the process comprises the steps of: step (A):reacting an amidine compound of Formula (II), or a salt thereof

with an aldehyde compound of Formula (III)

and a compound of Formula (IVa)

in a first organic solvent to obtain a compound of Formula (Va),

wherein R^(3b) is methoxy or ethoxy; and R^(3a) is H or C₁₋₃ alkyl; step(B): halogenating the compound of Formula (Va) in a third organicsolvent to form a halide; and then reacting the halide with a compoundof Formula (VI), or a salt thereof to obtain a compound of Formula(VIIa),

and step (C): forming the compound of Formula (I) or Formula (Ia) fromthe compound of Formula (VIIa) by means of a transesterification.
 2. Theprocess of claim 1, wherein the dihydropyrimidine compound has Formula(I-1), or a tautomer thereof having Formula (Ia-1),

wherein, each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)); andeach R^(7a) and R⁷ is independently H, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸.
 3. The process of claim 2,wherein the dihydropyrimidine compound has Formula (I-2), or a tautomerthereof having Formula (Ia-2),

wherein R¹ is F or Cl; and R² is Cl or Br.
 4. The process of claim 1,wherein R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, or butyl; Zis —O—, —S—, or —N(CH₃)—; Y is —O—, —S—, —S(═O)₂—, or —(CH₂)_(q)—; eachR⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); eachR^(7a) and R⁷ is independently H, methyl, ethyl, trifluoromethyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; each R⁸ and R^(8a) isindependently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy,C₁₋₄ alkyl-S(═O)₂—, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl,isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl,triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropyl-S(═O)₂—, cyclobutyl-S(═O)₂—,cyclopentyl-S(═O)₂—, cyclohexyl-S(═O)₂—, naphthyl-S(═O)₂—,phenyl-S(═O)₂—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or—(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; R^(3b) is methoxy or ethoxy; and R^(3a)is H, methyl, ethyl, isopropyl, or propyl.
 5. The process of claim 1,wherein the reaction in step (A) is performed at a temperature from 25°C. to 154° C. or from 60° C. to 100° C.
 6. The process of claim 1,wherein the step (A) further comprises a step of cooling the resultingcompound of Formula (Va) of step (A) to obtain a solid compound ofFormula (Va) at a cooling temperature from −40° C. to 40° C. or from 25°C. to 40° C.
 7. The process of claim 6, wherein the cooling is performedfor a period of from 0 hour to 24 hours, or from 1 minute to 24 hours,or from 1 hour to 8 hours.
 8. The process of claim 1, wherein the firstorganic solvent is applied in an amount of 0 equivalent to 80equivalents, or 1 equivalent to 20 equivalents per 1 equivalent byweight of the amidine compound of Formula (II), or a salt thereof. 9.The process of claim 1, wherein step (A) further comprises a step ofpurifying the compound of Formula (Va) in a second organic solvent,wherein the compound of Formula (Va) is purified by at least one of thefollowing methods: (1) trituration, wherein the trituration is carriedout at a temperature from −20° C. to 50° C. or from 0° C. to 40° C.; (2)recrystallization, wherein the recrystallization comprises acrystallization process at a temperature from −30° C. to 40° C. or from0° C. to 40° C., and wherein the recrystallization comprises acrystallization process of from 1 hour to 20 hours or from 1 hour to 10hours; or (3) washing, wherein the washing is performed at a temperaturefrom 0° C. to 30° C.
 10. The process of claim 9, wherein the secondorganic solvent is applied in an amount of 2 equivalent to 20equivalents per 1 equivalent by weight of the amidine compound ofFormula (II), or a salt thereof.
 11. The process of claim 9, whereineach of the first organic solvent and the second organic solvent isindependently a C₁₋₄ alcohol, a C₁₋₄ alcohol-water mixture, acetone,diethyl ether, isopropyl ether, petroleum ether, tetrahydrofuran,acetonitrile, cyclopentane, cyclohexane, n-hexane, a C₁₋₄ haloalkanesolvent, ethyl acetate, trifluoroethanol, 2-methoxyethanol,1,2-dimethoxyethane, 2-methoxyethyl ether, N,N-dimethyl formamide,N-methylpyrolidone, or a combination thereof, or wherein each of thefirst organic solvent and the second organic solvent is independentlymethanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, anethanol-water mixture at a volume ratio of from 10:90 to 90:10, acetone,tetrahydrofuran, N-methylpyrolidone, trifluoroethanol, 2-methoxyethanol,1,2-dimethoxyethane, 2-methoxyethyl ether, ethyl acetate, glycol,N,N-dimethyl formamide, or a combination thereof.
 12. The process ofclaim 1, wherein the third organic solvent is one or more C₁₋₄ alcohols,one or more C₁₋₄ haloalkanes, acetonitrile, isopropyl ether, petroleumether, toluene, xylene, tetrahydrofuran, ethyl acetate, acetone, or acombination thereof, or wherein the third organic solvent isdichloromethane, chloroform, tetrachloromethane, acetonitrile, isopropylether, petroleum ether, tetrahydrofuran, methanol, ethanol, propanol,i-propanol, n-butanol, tert-butanol, ethyl acetate, acetone, or acombination thereof.
 13. The process of claim 1, wherein thehalogenating reaction in step (B) is carried out in the presence of ahalogenating agent, and wherein the halogenating agent isN-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide,1,3-dibromo-5,5-dimethylhydantoin, or1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof.
 14. Theprocess of claim 1, wherein the transesterification in step (C) isperformed in the presence of a base, and wherein the base is formed byreacting lithium, sodium, or potassium or a combination thereof with aC₁₋₄ alcohol.
 15. The process of claim 14, wherein the C₁₋₄ alcohol ismethanol, ethanol, propanol, i-propanol, n-butanol, i-butanol, ortert-butanol, and wherein the lithium, sodium or potassium or acombination thereof is applied in an amount of 2 equivalents to 6equivalents per 1 equivalent by mole of the compound of Formula (VIIa).16. The process of claim 1, wherein the compound of Formula (IVa) instep (A) is prepared by a process comprising reacting a compound ofFormula (VIIIa) with a compound of Formula (IX),


17. A compound having Formula (Va), or a tautomer thereof having Formula(Va1), or a salt thereof, or a combination thereof,

wherein each R¹ and R² is independently F, Cl, or Br; R^(3b) is methoxyor ethoxy; R^(3a) is H or C₁₋₃ alkyl; each R⁹ is independently H, halo,C₁₋₄ alkyl, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,—(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸; eachR^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together withthe carbon atom to which they are attached, form a C₃₋₆ cycloalkylgroup, C₂₋₉ heterocyclyl group, or —(C═O)—; each R⁸ and R^(8a) isindependently H, C₁₋₄ alkyl, amino-C₁₋₄-alkyl, C₁₋₄ alkoxy, C₁₋₆alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₃₋₆ cycloalkyl, C₂₋₉heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆cycloalkyl-C₁₋₄-alkyl, C₂₋₉ heterocyclyl-C₁₋₆-alkyl, C₂₋₉heterocyclyl-S(═O)_(q)—, C₁₋₉ heteroaryl-S(═O)_(q)—, C₃₋₆cycloalkyl-S(═O)_(q)—, C₆₋₁₀ aryl-S(═O)_(q)—, —(CH₂)_(m)—OH,—(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; each mis independently 0, 1, 2, 3, or 4; R¹⁰ is H or deuterium; f is 1, 2, 3,or 4; j is 0, 1, or 2; Z is —O—, —S—, —S(═O)_(t), or —N(R⁴)—; t is 0, 1,or 2; and R⁴ is H or C₁₋₄ alkyl.
 18. The compound of claim 17 havingFormula (Va-1), or a tautomer thereof having Formula (Va1-1), or a saltthereof, or a combination thereof,


19. The compound of claim 17 having Formula (Va-2), or a tautomerthereof having Formula (Va1-2), or a salt thereof, or a combinationthereof,

wherein R¹ is F or Cl; and R² is Cl or Br; Z is —O—, —S—, or —N(CH₃)—;R^(3b) is methoxy or ethoxy; and R^(3a) is H, methyl, ethyl, isopropyl,or propyl.
 20. A process for preparing a dihydropyrimidine compoundhaving Formula (I), or a tautomer thereof having Formula (Ia),

wherein each R¹ and R² is independently F, Cl, or Br; R³ is C₁₋₄ alkyl;Z is —O—, —S—, —S(═O)_(t), or —N(R⁴)—; Y is —O—, —S—, —S(═O)_(t),—(CH₂)q-, or —N(R⁵)—; each t and q is independently 0, 1, or 2; each ofR⁴ and R⁵ is independently H or C₁₋₄ alkyl; each R⁶ is independently H,deuterium, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄ alkylamino,C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl, —(CR⁷R^(7a))_(m)—OH,—(CR⁷R^(7a))_(m)—C(═O)O—R⁸, —(CR⁷R^(7a))_(t)—N(R^(8a))₂,—S(═O)_(q)OR^(8a), —(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); eachR^(7a) and R⁷ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or—(CH₂)_(m)—C(═O)O—R⁸; or R^(7a) and R⁷, together with the carbon atom towhich they are attached, form a C₃₋₆ cycloalkyl group, C₂₋₉ heterocyclylgroup, or —(C═O)—; each R⁸ and R^(8a) is independently H, C₁₋₄ alkyl,amino-C₁₋₄-alkyl, C₁₋₄ alkoxy, C₁₋₆ alkyl-S(═O)_(q)—, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₃₋₆ cycloalkyl, C₂₋₉ heterocyclyl, C₆₋₁₀ aryl-C₁₋₆-alkyl,C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₆ cycloalkyl-C₁₋₄-alkyl, C₂₋₉heterocyclyl-C₁₋₆-alkyl, C₂₋₉ heterocyclyl-S(═O)_(q)—, C₁₋₉heteroaryl-S(═O)_(q)—, C₃₋₆ cycloalkyl-S(═O)_(q)—, C₆₋₁₀aryl-S(═O)_(q)—, —(CH₂)_(m)—OH, —(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or—(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; each R⁹ is independently H, halo, C₁₋₄alkyl, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,—(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)), or —(CR⁷R^(7a))_(m)—C(═O)O—R⁸; R¹⁰is H or deuterium; n is 0, 1, 2, 3, 4, or 5; each m is independently 0,1, 2, 3, or 4; f is 1, 2, 3, or 4; and j is 0, 1, or 2; wherein theprocess comprises the steps of: step (1): reacting an amidine compoundof Formula (II), or a salt thereof

with an aldehyde compound of Formula (III)

and a compound of Formula (IVa)

to obtain a compound (Va),

step (2): forming a compound of Formula (X) from a compound of Formula(Va) by means of a transesterification,

wherein R^(3b) is methoxy or ethoxy; and R^(3a) is H or C₁₋₃ alkyl; andstep (3): halogenating the compound of Formula (X) in a fourth organicsolvent to form a halide; and then reacting the halide with a compoundof Formula (VI), or a salt thereof to obtain a compound of Formula (I)or Formula (Ia),


21. The process of claim 20, wherein the dihydropyrimidine compound hasFormula (I-1), or a tautomer thereof having Formula (Ia-1),

wherein, each R⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,amino, C₁₋₄ alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(t)—N(R^(8a))₂, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)N(R⁸R^(8a)); andeach R^(7a) and R⁷ is independently H, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—(CH₂)_(m)—OH, or —(CH₂)_(m)—C(═O)O—R⁸.
 22. The process of claim 21,wherein the dihydropyrimidine compound has Formula (I-2), or a tautomerthereof having Formula (Ia-2),

wherein R¹ is F or Cl; and R² is Cl or Br.
 23. The process of claim 20,wherein R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, or butyl; Zis —O—, —S—, or —N(CH₃)—; Y is —O—, —S—, —S(═O)₂—, or —(CH₂)_(q)—; eachR⁶ is independently H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₄alkylamino, C₁₋₄ alkoxy, nitro, triazolyl, tetrazyl,—(CR⁷R^(7a))_(m)—OH, —S(═O)_(q)OR^(8a),—(CR⁷R^(7a))_(m)—S(═O)_(q)N(R^(8a))₂, —(CR⁷R^(7a))_(t)—N(R^(8a))₂,—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)O—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—OC(═O)—R⁸,—(CR⁷R^(7a))_(m)—C(═O)O—(CR⁷R^(7a))_(m)—C(═O)O—R⁸,—(CR⁷R^(7a))_(m)—OC(═O)—R⁸, or —(CR⁷R^(7a))_(m)—C(═O)—N(R⁸R^(8a)); eachR^(7a) and R⁷ is independently H, methyl, ethyl, trifluoromethyl, or—(CH₂)_(m)—C(═O)O—R⁸; each R⁸ and R^(8a) is independently H, methyl,ethyl, propyl, isopropyl, aminomethyl, methoxy, C₁₋₄ alkyl-S(═O)₂—,phenyl, pyridyl, thiazolyl, furanyl, imidazolyl, isoxazolyl, oxazolyl,pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl,thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl,pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropyl-S(═O)₂—, cyclobutyl-S(═O)₂—, cyclopentyl-S(═O)₂—,cyclohexyl-S(═O)₂—, naphthyl-S(═O)₂—, phenyl-S(═O)₂—, —(CH₂)_(m)—OH,—(CH₂)_(m)—C(═O)O—(CH₂)_(m)—H, or —(CH₂)_(m)—OC(═O)—(CH₂)_(m)—H; R^(3b)is methoxy or ethoxy; and R^(3a) is H, methyl, ethyl, isopropyl, orpropyl.
 24. The process of claim 20, wherein the transesterification instep (2) is performed in the present of a base, wherein the base isformed by reacting lithium, sodium, or potassium or a combinationthereof with a C₁₋₄ alcohol, wherein the C₁₋₄ alcohol is methanol,ethanol, propanol, i-propanol, n-butanol, i-butanol, or tert-butanol,and wherein the lithium, sodium, potassium or a combination thereof isapplied in an amount of 2 equivalents to 8 equivalents per 1 equivalentby mole of the compound of Formula (Va).
 25. The process of claim 20,wherein the fourth organic solvent is one or more C₁₋₄ alcohols, one ormore C₁₋₄ haloalkanes, ethyl acetate, acetonitrile, isopropyl ether,petroleum ether, toluene, xylene, tetrahydrofuran, acetone, or acombination thereof, or the forth organic solvent is methanol, ethanol,propanol, i-propanol, n-butanol, tert-butanol, dichloromethane,chloroform, tetrachloromethane, ethyl acetate, acetonitrile, isopropylether, petroleum ether, tetrahydrofuran, acetone, or a combinationthereof.
 26. The process of claim 20, wherein the halogenating reactionin step (3) is carried out in the presence of a halogenating agent, andwherein the halogenating agent is N-bromosuccinimide,N-chlorosuccinimide, N-iodosuccinimide,1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin,or a combination thereof.
 27. The process of claim 10, wherein each ofthe first organic solvent and the second organic solvent isindependently a C₁₋₄ alcohol, a C₁₋₄ alcohol-water mixture, acetone,diethyl ether, isopropyl ether, petroleum ether, tetrahydrofuran,acetonitrile, cyclopentane, cyclohexane, n-hexane, a C₁₋₄ haloalkanesolvent, ethyl acetate, trifluoroethanol, 2-methoxyethanol,1,2-dimethoxyethane, 2-methoxyethyl ether, N,N-dimethyl formamide,N-methylpyrolidone, or a combination thereof, or wherein each of thefirst organic solvent and the second organic solvent is independentlymethanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, anethanol-water mixture at a volume ratio of from 10:90 to 90:10, acetone,tetrahydrofuran, N-methylpyrolidone, trifluoroethanol, 2-methoxyethanol,1,2-dimethoxyethane, 2-methoxyethyl ether, ethyl acetate, glycol,N,N-dimethyl formamide, or a combination thereof.